scholarly journals Drug-induced Thrombotic Microangiopathy During Maintenance Treatment in a Patient With Multiple Myeloma

HemaSphere ◽  
2019 ◽  
Vol 3 (3) ◽  
pp. e192 ◽  
Author(s):  
Víctor Higuero Saavedra ◽  
Verónica González-Calle ◽  
Eduardo Sobejano ◽  
Josefa Sebastiá ◽  
Mónica Cabrero ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Thrombotic Microangiopathy ◽  
Maintenance Treatment ◽  
Drug Induced

Carfilzomib-induced thrombotic microangiopathy. A case report

2021 ◽  
pp. 107815522110674
Author(s):  
Valentina Scheggi ◽  
Irene Merilli ◽  
Edoardo Cesaroni ◽  
Bruno Alterini
Keyword(s):  
Multiple Myeloma ◽  
Case Report ◽  
Thrombotic Microangiopathy ◽  
Proteasome Inhibitors ◽  
Causal Association ◽  
Drug Induced ◽  
General Outcome ◽  
Life Threatening ◽  
Drug Dependent ◽  
New Onset

Introduction Drug-induced thrombotic microangiopathy (DITMA) is an acquired condition resulting from exposure to a drug that induces the formation of platelet-rich thrombi in small arterioles or capillaries secondary to drug-dependent antibodies or direct tissue toxicity. Carfilzomib is a selective proteasome inhibitor approved to treat selected patients with Multiple Myeloma (MM). It is one of the drugs with the strongest evidence for a causal association with non-antibody-mediated DITMA. Case Report A 75-year-old man presented to the emergency department for the outbreak of vomit, asthenia, oliguria and dark stool emission. He was recently diagnosed with multiple myeloma, treated with lenalidomide, dexamethasone and carfilzomib. Laboratory exams were significant for microangiopathic haemolytic anaemia, thrombocytopenia and new-onset renal failure. ADAMTS-13 levels were in range, and no infectious signs were found both in blood nor in stool test. Management & Outcome A carfilzomib induced thrombotic microangiopathy was soon suspected. Thus, since daily haemodialysis and supportive care did not seem to get a fast enough recovery, the patient was treated with eculizumab with a good general outcome. Discussion Drug-induced thrombotic microangiopathy is a rare and often life-threatening acquired condition whose diagnosis can be challenging and whose therapy is not always limited to supportive treatment and drug avoidance. Carfilzomib, along with other proteasome inhibitors, is one of the described potential drugs which can trigger such a manifestation.

scholarly journals CCL2 Promotes Macrophages-Associated Chemoresistance Via MCPIP1 Dual Catalytic Activities in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3086-3086
Author(s):  
Ruyi Xu ◽  
Yi Li ◽  
Haimeng Yan ◽  
Xi Huang ◽  
He Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Sequencing ◽  
Clinical Significance ◽  
Drug Induced ◽  
Stat3 Pathway ◽  
Catalytic Activities ◽  
Knock Down ◽  
Chemotherapy Drug ◽  
Ccl2 Expression ◽  
Induced Apoptosis

Background: Despite with the introduction of novel chemotherapy agents to multiple myeloma (MM), chemoresistance remains the major problem in clinical management. The interaction of MM cells with different cell components in the tumor microenvironment is important for tumor growth and chemoresistance, in which macrophages (Mφs) represent the prominent components. Mφs, who provide a favorable microenvironment for MM cells, protect them from drug-induced apoptosis. Mφs have great plasticity and can differentiate into different functional states according to microenvironmental signals. We previously found that the chemokine CCL2 is overexpressed in MM patients and CCL2 promoted Mφs'infiltration in the MM-BM microenvironment. The present study aims to further investigate the clinical significance of CCL2 and elucidate the mechanism how it participates in Mφs-mediated MM chemoresistance. Methods: Clinical significance of CCL2 were investigated by immunohistochemistry and Elisa. Flow cytometry, quantitative real-time PCR and Western blotting were conducted to evaluated the apoptosis of MM cells and Mφs' polarization. RNA sequencing was performed to determine the key molecular induced by CCL2 in Mφs. Genetically modified cells (e.g., exhibiting siRNA knockdown, generating deletion mutants through lentiviruses) were employed to evaluate the functional significance of MCPIP1. Proteome Profiler Human phosphor-kinase antibody array was used to determine the changes of protein phosphorylation in Mφs caused by CCL2. MM xenograft models were used to evaluated the role of CCL2 and MCPIP1 in vivo. Results: We found that CCL2 expression is tightly associated with MM patients' treatment status. When newly diagnosed patients received 4 courses of PCD combined therapy, CCL2 expression in their BM significantly decreased. MM cell lines and PBMCs barely expressed CCL2, while Mφs highly expressed CCL2. Mφs interacted with MM cells further upregulated their expression of CCL2. These increased CCL2 in the MM' BM microenvironment had little effect on MM cells' proliferation and their drug responses, but CCL2-treated Mφs were more effective at protecting MM cells from bortezomib- and melphalan- induced apoptosis. CCL2 could also effectively polarize Mφs toward M2-like Mφs, which possess a stronger ability to protect MM cells from chemotherapy drug-induced apoptosis. RNA sequencing revealed that CCL2 significantly induced the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in Mφs and the result was verified both in mRNA and protein level. MM cells cocultured with MCPIP1-knock down Mφs were more sensitive to drug-induced apoptosis than those cocultured with control Mφs. Mφs transfected with D141N mutant MCPIP1 lost their protective effects because the mutation resulted in impaired RNase and DUB activities of MCPIP1. Mφs isolated from NSG mice' tumor masses showed MCPIP1-knock down Mφs displayed a more M1-like phenotype and in vitro experiments showed MCPIP1-knock down Mφs were more difficult to be polarized toward M2-like Mφs by MM cells. CCL2 significantly activated JAK2/STAT3 pathway in Mφs and inhibition of STAT3 hindered CCL2-induced MCPIP1 protein expression. Conclusion: Our study showed that increased CCL2 in MM' BM microenvironment polarizes Mφs towards M2-like phenotype and promotes Mφs to protect MM cells from chemotherapy drug-induced apoptosis. Mechanistically, CCL2 activated JAK2/STAT3 pathway to induce the expression of MCPIP1. MCPIP1, the critical negative regulator of inflammation, mediated Mφs 'polarization and protection effect via its dual catalytic activities. Key words: Multiple Myeloma, Macrophages-Associated Chemoresistance, Polarization, CCL2, MCPIP1 Disclosures No relevant conflicts of interest to declare.

Patient preferences for interferon alfa in multiple myeloma.

1997 ◽  
Vol 15 (4) ◽  
pp. 1672-1679 ◽  
Author(s):  
H Ludwig ◽  
E Fritz ◽  
J Neuda ◽  
B G Durie
Keyword(s):  
United States ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Patient Preferences ◽  
Maintenance Treatment ◽  
The United States ◽  
Interferon Alfa ◽  
Medical Decision ◽  
Published Data ◽  
Financial Cost

PURPOSE Interferon alfa treatment in multiple myeloma marginally improves relapse-free and overall survival. Often it does so at the expense of toxicity and financial cost. If patients are unwilling or unable to participate in the decision of whether to initiate such treatment, known patient preferences can serve as guidelines for the physician. We interviewed myeloma patients in the United States to obtain information that might facilitate medical decision-making. PATIENTS AND METHODS Three hundred fifty-five myeloma patients throughout the United States were interviewed by telephone. Without identifying interferon alfa as the treatment agent, interviewers described potential adverse effects, financial cost, and self-injection procedures. The potential benefits of four treatment choices, derived from a meta-analysis of published data, were presented as gains in remission rate (+10%), remission duration (an additional 4 and 7 months, respectively, for induction and maintenance treatment), and overall survival (an additional 3 and 6 months, respectively, for induction and maintenance treatment). Patients' choices for or against use of the unidentified substance were recorded, and interferon was subsequently disclosed as the treatment. The profiles of patients making different choices were determined using multivariate regression techniques. RESULTS Approximately half of the patients accepted the unidentified treatment if remission and/or survival improved by at least 6 months. Accepters were younger and more likely to have used interferon. Of patients who rejected the unidentified treatment, 25% to 50% would have been willing to accept it if the benefits were > or = 12 months. Test/retest reliability of all choices, determined in 36 cancer patients, was 0.896. CONCLUSION In multiple myeloma, interferon therapy and, by inference, other treatments with comparable features are acceptable to approximately half of the patients if a 6-month gain in relapse-free or overall survival can be expected.

Addressing Unmet Medical Needs in Maintenance Treatment for Newly Diagnosed Multiple Myeloma (NDMM)

2018 ◽  
Vol 18 ◽  
pp. S248-S249
Author(s):  
Sagar Lonial ◽  
Wee Joo Chng ◽  
Meral Beksac ◽  
Roman Hajek ◽  
Katja Weisel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Treatment ◽  
Newly Diagnosed ◽  
Medical Needs ◽  
Unmet Medical Needs

Abstract 1734: Drug- induced generation of Mcl-1128-350fragment triggers apoptosis in multiple myeloma cells through upregulation of c-Jun.

2013 ◽  
Author(s):  
Fengjuan Fan ◽  
Giovanni Tonon ◽  
Martin Sattler ◽  
Hartmut Goldschmidt ◽  
Joseph Opferman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Induced ◽  
Myeloma Cells

scholarly journals A case of bortezomib-associated thrombotic microangiopathy in a multiple myeloma patient

2019 ◽  
Vol 4 (1-2) ◽  
pp. 46-51
Author(s):  
Nuno Moreira Fonseca ◽  
Filipa Cardoso ◽  
Manuel Monteiro ◽  
Mário Góis ◽  
Helena Sousa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Thrombotic Microangiopathy ◽  
First Generation ◽  
Kidney Biopsy ◽  
Drug Discontinuation ◽  
Pathophysiological Mechanism ◽  
Fatal Complication ◽  
Multiple Myeloma Patient ◽  
High Index Of Suspicion ◽  
Concurrent Medication

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma. We present a case of a 70-year-old woman with multiple myeloma, who presented thrombotic microangiopathy with multi-organ involvement thrombotic microangiopathy (ocular, cardiac, and renal) after bortezomib initiation. A kidney biopsy confirmed the diagnosis of thrombotic microangiopathy. A temporal relation between bortezomib exposure and thrombotic microangiopathy onset was seen in the absence of other concurrent medication or disease known to cause thrombotic microangiopathy, and thrombotic microangiopathy was only resolved after drug discontinuation. The exact pathophysiological mechanism remains unknown. To our knowledge, this is the second biopsy-proven published case of bortezomib-associated thrombotic microangiopathy. Since bortezomib is extensively used for treating patients with multiple myeloma, prescribing clinicians should maintain a high index of suspicion of this potentially fatal complication.

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