Two cases of proteasome inhibitors related thrombotic microangiopathies and literature review

Two cases of proteasome inhibitors related thrombotic microangiopathies and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Two cases of proteasome inhibitors related thrombotic microangiopathies and literature review Na An, Pengfei Shi, Can Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7388047/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Multiple myeloma (MM) is a prevalent hematological malignancy, with proteasome inhibitors (PIs) playing a crucial role in its therapeutic management. Although PIs are generally well-tolerated and associated with relatively mild side effects, recent evidence has increasingly drawn attention to proteasome inhibitor-related thrombotic microangiopathy (PI-related TMA). Case presentation Here, we report two clinical cases of PI-related TMA, highlighting the diagnostic process and subsequent management strategies. Confirmation of PI-related TMA prompted the discontinuation of the offending agent and consideration of plasma exchange therapy, which proved beneficial in selected patients. These case reports further facilitate a detailed discussion regarding the underlying pathogenic mechanisms and potential therapeutic approaches for PI-related TMA in MM. Conclusion The diagnosis of PI-related TMA in MM patients poses significant challenges due to overlapping clinical features between MM itself and TMA. The condition often presents insidiously but carries a severe prognosis, underscoring the necessity for prompt diagnosis and immediate therapeutic intervention. Multiple Myeloma proteasome inhibitor thrombotic microangiopathy Figures Figure 1 Introduction Multiple myeloma (MM) is a common hematological malignancy predominantly affecting elderly individuals. Despite notable therapeutic advancements, MM remains incurable. However, recent advances have improved the 5-year survival rate to approximately 52.2%, primarily attributed to the introduction and widespread clinical application of novel therapeutic agents[ 1 ]. Consequently, MM patients often experience adverse drug reactions due to multi-drug regimens. Proteasome inhibitors (PIs) currently represent a cornerstone of MM therapy. Although renal impairment is frequently observed in MM patients, this complication is usually attributed to disease progression or adverse effects from other medications, such as immunomodulators. Differentiating the cause of severe thrombocytopenia and renal impairment remains clinically challenging, especially in patients with MM. Thrombotic microangiopathy (TMA) is a hematological syndrome characterized by endothelial damage and activation of the coagulation cascade, resulting in thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction, predominantly affecting the kidneys[ 2 ]. Drug-induced TMA (DITMA), although rare, represents a serious complication that can lead to rapid deterioration of renal function[ 3 ]. Historically, PIs have not commonly been associated with TMA; however, emerging evidence increasingly recognizes PIs as potential causative agents in some TMA cases[ 4 ]. In this report, we present two clinical cases of PI-related TMA, systematically elaborating on the clinical characteristics, potential pathogenic mechanisms, and therapeutic strategies. Cases presentations Case 1 A 53-year-old female patient presented in February 2023 with a six-month history of fatigue. Bone marrow examination revealed 46% primitive and immature plasma cells, with flow cytometry identifying 41.6% abnormal clonal plasma cells. Bone marrow biopsy confirmed plasma cell myeloma negative for Congo Red staining, with cytogenetic analysis revealing a 1q21 + aberration. The patient was diagnosed with IgG-K MM, classified as R-ISS stage III. She had no prior history of diabetes or hypertension, and her blood pressure at admission was 142/82 mmHg. Chemotherapy commenced on February 27th, 2023, using a CyBorD regimen (cyclophosphamide, bortezomib, and dexamethasone) due to existing renal insufficiency. Initial treatment was uneventful until March 4th, when creatinine levels sharply increased to 356 mmol/L. Despite discontinuation of cyclophosphamide, renal function worsened, and the patient required hemodialysis due to progressively declining urine output. Platelet count dropped significantly, accompanied by poorly controlled hypertension and severe generalized edema. On March 25th, the patient developed acute severe abdominal pain, hypotension, anemia, thrombocytopenia, elevated inflammatory and cardiac biomarkers, and positive fecal occult blood. Abdominal CT indicated extensive intestinal edema and multiple effusions. Given the clinical suspicion of TMA, a blood smear identified 2% schistocytes, although ADAMTS13 testing returned negative. Upon reviewing the patient's medication history and progression of her disease, no significant factors other than PI drugs were identified that could have triggered the thrombotic microangiopathy (TMA). The correlation between the worsening of symptoms and the administration of PI drugs was notably consistent with each exposure (as illustrated in Fig. 1 ). Particularly, the timing of symptom exacerbation closely matched the median onset time for PI drug-induced TMA. This strong temporal association suggested that the PI medications were likely responsible for the patient's TMA. Emergency plasma exchange therapy significantly improved clinical symptoms, urine output, blood pressure, and platelet counts. Subsequent complement testing (Sc5b-9) confirmed complement-mediated TMA. After a series of 11 plasma exchange sessions and cessation of PI therapy, renal function and platelet counts stabilized, with complement levels normalizing by May 2023. Chemotherapy was adjusted to daratumumab plus dexamethasone, effectively controlling TMA. Case 2 In March 2025, a 76-year-old female patient was diagnosed with high-risk IgG-λ MM characterized by multiple relapses and disease progression despite intensive treatment for over one year. She previously participated in the QLS32015 clinical trial, briefly achieving remission but subsequently developing new skeletal lesions. Bone marrow biopsy revealed 46.5% clonal plasma cells, and cytogenetic studies confirmed 1q21 amplification and t(4;14)(p16;q32). Radiological imaging demonstrated progressive skeletal lesions, including new bone destruction in the right fibula and humeral head, with exacerbation of iliac bone damage. Laboratory results indicated elevated serum IgG (57.60 g/L), suppressed IgA and IgM levels, significantly elevated free lambda light chains (88.20 g/L), profound thrombocytopenia (15×10^9/L), and raised β2-microglobulin (6569.0 µg/L). The patient was initiated on carfilzomib, aponermin, and dexamethasone chemotherapy. Soon after initiation, she experienced severe hypertension (peak 191/114 mmHg) and severe headaches responsive only temporarily to antihypertensive treatments. On day four, the patient developed uncontrollable limb convulsions lasting nearly two hours, resistant to antiepileptic therapy. Head CT excluded hemorrhage, cerebral infarction, and space-occupying lesions. Laboratory data revealed elevated inflammatory markers, anemia, thrombocytopenia, mild schistocytosis (3%), and normal fibrinogen levels excluding DIC. The absence of diarrhea history ruled out hemolytic uremic syndrome (HUS). Despite the absence of ADAMTS13 testing, thrombotic thrombocytopenic purpura (TTP) was considered unlikely due to hypertension. These findings supported a diagnosis of carfilzomib-related TMA. The patient chose to discontinue treatment and was discharged upon request. Post-discharge, her seizure symptoms improved; however, she passed away one month later. Discussion and conclusions Multiple myeloma (MM) is a malignant clonal disorder of plasma cells, often accompanied by excessive production of immunoglobulin heavy or light chains. Its clinical manifestations typically include renal failure, hypercalcemia, symptomatic anemia, and osteolytic bone lesions. TMA and MM can present with overlapping clinical features, complicating diagnosis, especially since TMA may involve multiple organ systems beyond hematologic abnormalities. The kidney is the most frequently involved organ after the hematological system. Manifestations such as elevated creatinine, proteinuria, oliguria, and hypertension may suggest renal involvement in TMA[ 5 ]. Importantly, newly developed proteinuria and worsening hypertension—especially when unexplained by other causes—should prompt consideration of TMA. However, as these features are also common in MM itself, their diagnostic value is limited without further supporting evidence. Several reports have described PI-related TMA affecting diverse organ systems. For instance, Leung et al. found that among 11 patients with confirmed PI-related TMA, three exhibited central nervous system symptoms and six had gastrointestinal involvement[ 6 ]. In our study, one patient experienced severe abdominal pain and bloody stools, potentially attributable to TMA-related intestinal ischemia. Though pulmonary involvement in TMA is rare, cases of pulmonary arterial hypertension and hypoxia have been reported[ 7 ]. In our cohort, pleural effusion and multiple serous cavity effusions further supported the diagnosis. While extra-renal manifestations are non-specific, their presence during PI therapy should raise suspicion for TMA. In the first case, the patient initially presented with significant renal impairment; however, her daily urine output at admission was stable at approximately 1500–2000 mL. Over the subsequent two weeks, her renal function deteriorated progressively, yet platelet and hemoglobin levels remained at baseline, initially attributed to disease progression. Renal impairment is a common complication in MM, affecting approximately 20%-50% of patients either at diagnosis or during disease progression. Half of these cases are reversible, while around 2%-12% require renal replacement therapy[ 3 ]. The patient's continuous rise in creatinine and decline in urine output prompted consideration of dialysis. However, concurrent thrombocytopenia and hypertension raised further diagnostic concerns. Although bortezomib may cause thrombocytopenia, typically it is mild. Additional symptoms such as severe abdominal pain, bloody stools, elevated D-dimer levels, and inconsistent clinical and imaging findings led to the diagnosis of ischemic bowel disease, ultimately contributing to the suspicion of TMA. In the second case, hypertension and neurological symptoms following carfilzomib administration, combined with the presence of fragmented red blood cells, significantly heightened the suspicion of TMA. Thrombocytopenia, renal dysfunction, and thrombosis are critical indicators of TMA, further supported by increased schistocytes in peripheral blood. The patient developed TMA in the absence of active infection and in the context of disease remission, strongly implicating drug-induced TMA. Additionally, the patient had no prior exposure to known TMA-inducing drugs, and the temporal correlation between clinical deterioration and proteasome inhibitor use was evident. PI-related TMA is clinically rare but carries substantial mortality and morbidity risks, including the potential need for long-term renal replacement therapy. Thus, early identification and effective management are critical for minimizing irreversible organ damage. Immediate cessation of the implicated drug is essential upon diagnosis. Drug rechallenge can lead to TMA recurrence, confirming its causative role, and thus should generally be avoided to prevent recurrent episodes. Eculizumab, a monoclonal antibody approved for the treatment of atypical hemolytic uremic syndrome, has also been used in the management of PI-related TMA in four reported cases, with two achieving clinical cure. Literature suggests that approximately 14.9% of PI-related TMA cases result in adverse outcomes[ 7 , 8 , 9 , 10 ]. Emerging data increasingly link complement system abnormalities, particularly in patients with mutations in complement regulatory genes, to carfilzomib-induced TMA. Therefore, such patients should be considered high-risk. Testing for the complement complex component Sc5b-9 may support the diagnosis of suspected PI-related TMA[ 11 , 12 ]. In cases where complement activation is suspected, early administration of eculizumab is recommended to target the underlying pathophysiology effectively[ 12 ]. The therapeutic benefit of therapeutic plasma exchange (TPE) remains debatable, especially in cases of carfilzomib-related TMA, where patients may derive limited benefit[ 13 ]. In our case, although the patient responded well to TPE, her improvement could also be attributed to the discontinuation of the causative drug. Initially, TPE was pursued out of concern for thrombotic thrombocytopenic purpura (TTP). Nonetheless, some studies suggest that TPE can improve hematologic parameters, supporting further exploration of its potential utility in managing PI-related TMA[ 14 ]. TMA is associated with a poor prognosis, and diagnosing PI-related TMA remains clinically challenging due to its nonspecific presentation and overlap with MM-related complications. As reports of PI-related TMA gradually increase, particularly in Western literature, clinicians in other regions, including China, should heighten their awareness of this potentially fatal complication. Currently, there are no validated predictive markers for identifying patients at risk of PI-related TMA before treatment initiation, necessitating vigilant monitoring. In summary, while no expert consensus exists on optimal treatment, both plasma exchange and eculizumab have shown promise. For patients with suspected complement activation, early administration of eculizumab may yield the best outcomes. Prompt recognition and discontinuation of the offending agent remain the cornerstone of effective management, underscoring the need for heightened clinical suspicion and a proactive therapeutic approach. Declarations Acknowledgements The authors would like to thank all individuals who provided support and assistance in this study. Author contributions Na Anand Can Chen analyzed the data and wrote the manuscript. Pengfei Shi conceived the study Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors Ethics approval and consent to participate Our institution does not require ethics approval for reporting individual cases or case series. Consent for publication Verbal informed consent was obtained from the patient for their information and images to be published anonymously in this article. Competing interests The authors declare no competing interests. References Moreau P, Attal M, Facon T. Frontline therapy of multiple myeloma. Blood. 2015;125(20):3076–84. 10.1182/blood-2014-09-568915 . Yui JC, Van Keer J, Weiss BM, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol. 2016;91(9):E348–52. 10.1002/ajh.24447 . Nguyen MN, Nayernama A, Jones SC, et al. Proteasome inhibitor-associated thrombotic microangiopathy: A review of cases reported to the FDA adverse event reporting system and published in the literature. Am J Hematol. 2020;95(9):E218–22. 10.1002/ajh.25832 . Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753–61. 10.3324/haematol.2013.089334 . Moore H, Romeril K. Multiple myeloma presenting with a fever of unknown origin and development of thrombotic thrombocytopenic purpura post-bortezomib. Intern Med J. 2011;41(4):348–50. 10.1111/j.1445-5994.2011.02458.x . Yui JC, Van Keer J, Weiss BM, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol. 2016;91(9):E348–52. 10.1002/ajh.24447 . Moscvin M, Liacos CI, Chen T, et al. Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy. Blood Cancer J. 2023;13(1):31. 10.1038/s41408-023-00802-0 . Bhutani D, Assal A, Mapara MY, et al. Case Report: Carfilzomib-induced Thrombotic Microangiopathy With Complement Activation Treated Successfully With Eculizumab. Clin Lymphoma Myeloma Leuk. 2020;20(4):e155–7. 10.1016/j.clml.2020.01.016 . Nguyen MN, Nayernama A, Jones SC, et al. Proteasome inhibitor-associated thrombotic microangiopathy: A review of cases reported to the FDA adverse event reporting system and published in the literature. Am J Hematol. 2020;95(9):E218–22. 10.1002/ajh.25832 . Higuero Saavedra V, González-Calle V, Sobejano E, et al. Drug-induced Thrombotic Microangiopathy During Maintenance Treatment in a Patient With Multiple Myeloma. Hemasphere. 2019;3(3):e192. 10.1097/HS9.0000000000000192 . Portuguese AJ, Gleber C, Passero FC Jr, et al. A review of thrombotic microangiopathies in multiple myeloma. Leuk Res. 2019;85:106195. 10.1016/j.leukres.2019.106195 . Chen C, Li Y, Shi P, et al. Proteasome inhibitors related thrombotic microangiopathy: a systematic and comprehensive review. Blood Cancer J. 2024;14(1):196. 10.1038/s41408-024-01182-9 . Monteith BE, Venner CP, Reece DE, et al. Drug-induced Thrombotic Microangiopathy with Concurrent Proteasome Inhibitor Use in the Treatment of Multiple Myeloma: A Case Series and Review of the Literature. Clin Lymphoma Myeloma Leuk. 2020;20(11):e791–800. 10.1016/j.clml.2020.04.014 . George JN, Li X, McMinn JR, et al. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44(2):294–304. 10.1111/j.1537-2995.2004.00700.x . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 Oct, 2025 Reviews received at journal 17 Sep, 2025 Reviewers agreed at journal 02 Sep, 2025 Reviews received at journal 02 Sep, 2025 Reviewers agreed at journal 28 Aug, 2025 Reviewers invited by journal 27 Aug, 2025 Editor assigned by journal 19 Aug, 2025 Submission checks completed at journal 19 Aug, 2025 First submitted to journal 16 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7388047","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":509314423,"identity":"4f853b43-c49e-4445-8af7-3b6a51192c43","order_by":0,"name":"Na An","email":"","orcid":"","institution":"Affiliated Hangzhou First People’s Hospital, Westlake University","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"An","suffix":""},{"id":509314424,"identity":"8698acbb-a65c-40a6-93f2-866a4821f231","order_by":1,"name":"Pengfei Shi","email":"","orcid":"","institution":"Affiliated Hangzhou First People’s Hospital, Westlake University","correspondingAuthor":false,"prefix":"","firstName":"Pengfei","middleName":"","lastName":"Shi","suffix":""},{"id":509314425,"identity":"534662f6-bdc9-48cd-bd85-c0e900e4ff34","order_by":2,"name":"Can Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBACNnbmBoYEhgMMDOyNjQ8/EKOFn5kRqoXncLOxBDFaJJuBWhhAWiTS2wR4iNFicJixTeJBzR05c8mHbQwSDHZyug3EaEk49szYcnZi24MChmRjswNEaLmR2HA4ccPtxHYDCYYDidsIabGHaqnfcPNgmwQPMVpgtiQY3GAkXkv7j4Rjhw03nEkEBrIBMX453nzY8EfNYXmD48cfPvxQYSdHUAu6CaQpHwWjYBSMglGAAwAAPylKeywKLlsAAAAASUVORK5CYII=","orcid":"","institution":"Affiliated Hangzhou First People’s Hospital, Westlake University","correspondingAuthor":true,"prefix":"","firstName":"Can","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-08-16 14:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7388047/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7388047/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90543689,"identity":"efd9a109-88b2-4132-a0a7-e601818ad1bb","added_by":"auto","created_at":"2025-09-04 00:13:55","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70891,"visible":true,"origin":"","legend":"\u003cp\u003eThe course of clinical and laboratory changes (A, Hemaglobin B, platelet, C, creatinine D, Lactate Dehydrogenase) in this patient.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7388047/v1/fa9e8e5f590da015789584f0.jpeg"},{"id":90543696,"identity":"7e6d1d4a-2d83-4a74-868d-98a31e5fad04","added_by":"auto","created_at":"2025-09-04 00:14:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":415139,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7388047/v1/60a6c473-3f35-47aa-a74e-80585be26831.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Two cases of proteasome inhibitors related thrombotic microangiopathies and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMultiple myeloma (MM) is a common hematological malignancy predominantly affecting elderly individuals. Despite notable therapeutic advancements, MM remains incurable. However, recent advances have improved the 5-year survival rate to approximately 52.2%, primarily attributed to the introduction and widespread clinical application of novel therapeutic agents[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Consequently, MM patients often experience adverse drug reactions due to multi-drug regimens. Proteasome inhibitors (PIs) currently represent a cornerstone of MM therapy. Although renal impairment is frequently observed in MM patients, this complication is usually attributed to disease progression or adverse effects from other medications, such as immunomodulators. Differentiating the cause of severe thrombocytopenia and renal impairment remains clinically challenging, especially in patients with MM.\u003c/p\u003e\u003cp\u003eThrombotic microangiopathy (TMA) is a hematological syndrome characterized by endothelial damage and activation of the coagulation cascade, resulting in thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction, predominantly affecting the kidneys[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Drug-induced TMA (DITMA), although rare, represents a serious complication that can lead to rapid deterioration of renal function[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Historically, PIs have not commonly been associated with TMA; however, emerging evidence increasingly recognizes PIs as potential causative agents in some TMA cases[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In this report, we present two clinical cases of PI-related TMA, systematically elaborating on the clinical characteristics, potential pathogenic mechanisms, and therapeutic strategies.\u003c/p\u003e"},{"header":"Cases presentations","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA 53-year-old female patient presented in February 2023 with a six-month history of fatigue. Bone marrow examination revealed 46% primitive and immature plasma cells, with flow cytometry identifying 41.6% abnormal clonal plasma cells. Bone marrow biopsy confirmed plasma cell myeloma negative for Congo Red staining, with cytogenetic analysis revealing a 1q21 + aberration. The patient was diagnosed with IgG-K MM, classified as R-ISS stage III. She had no prior history of diabetes or hypertension, and her blood pressure at admission was 142/82 mmHg. Chemotherapy commenced on February 27th, 2023, using a CyBorD regimen (cyclophosphamide, bortezomib, and dexamethasone) due to existing renal insufficiency.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eInitial treatment was uneventful until March 4th, when creatinine levels sharply increased to 356 mmol/L. Despite discontinuation of cyclophosphamide, renal function worsened, and the patient required hemodialysis due to progressively declining urine output. Platelet count dropped significantly, accompanied by poorly controlled hypertension and severe generalized edema.\u003c/p\u003e\u003cp\u003eOn March 25th, the patient developed acute severe abdominal pain, hypotension, anemia, thrombocytopenia, elevated inflammatory and cardiac biomarkers, and positive fecal occult blood. Abdominal CT indicated extensive intestinal edema and multiple effusions. Given the clinical suspicion of TMA, a blood smear identified 2% schistocytes, although ADAMTS13 testing returned negative.\u003c/p\u003e\u003cp\u003eUpon reviewing the patient's medication history and progression of her disease, no significant factors other than PI drugs were identified that could have triggered the thrombotic microangiopathy (TMA). The correlation between the worsening of symptoms and the administration of PI drugs was notably consistent with each exposure (as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Particularly, the timing of symptom exacerbation closely matched the median onset time for PI drug-induced TMA. This strong temporal association suggested that the PI medications were likely responsible for the patient's TMA.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eEmergency plasma exchange therapy significantly improved clinical symptoms, urine output, blood pressure, and platelet counts. Subsequent complement testing (Sc5b-9) confirmed complement-mediated TMA. After a series of 11 plasma exchange sessions and cessation of PI therapy, renal function and platelet counts stabilized, with complement levels normalizing by May 2023. Chemotherapy was adjusted to daratumumab plus dexamethasone, effectively controlling TMA.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eIn March 2025, a 76-year-old female patient was diagnosed with high-risk IgG-λ MM characterized by multiple relapses and disease progression despite intensive treatment for over one year. She previously participated in the QLS32015 clinical trial, briefly achieving remission but subsequently developing new skeletal lesions. Bone marrow biopsy revealed 46.5% clonal plasma cells, and cytogenetic studies confirmed 1q21 amplification and t(4;14)(p16;q32). Radiological imaging demonstrated progressive skeletal lesions, including new bone destruction in the right fibula and humeral head, with exacerbation of iliac bone damage. Laboratory results indicated elevated serum IgG (57.60 g/L), suppressed IgA and IgM levels, significantly elevated free lambda light chains (88.20 g/L), profound thrombocytopenia (15×10^9/L), and raised β2-microglobulin (6569.0 µg/L).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe patient was initiated on carfilzomib, aponermin, and dexamethasone chemotherapy. Soon after initiation, she experienced severe hypertension (peak 191/114 mmHg) and severe headaches responsive only temporarily to antihypertensive treatments.\u003c/p\u003e\u003cp\u003eOn day four, the patient developed uncontrollable limb convulsions lasting nearly two hours, resistant to antiepileptic therapy. Head CT excluded hemorrhage, cerebral infarction, and space-occupying lesions. Laboratory data revealed elevated inflammatory markers, anemia, thrombocytopenia, mild schistocytosis (3%), and normal fibrinogen levels excluding DIC. The absence of diarrhea history ruled out hemolytic uremic syndrome (HUS). Despite the absence of ADAMTS13 testing, thrombotic thrombocytopenic purpura (TTP) was considered unlikely due to hypertension. These findings supported a diagnosis of carfilzomib-related TMA. The patient chose to discontinue treatment and was discharged upon request. Post-discharge, her seizure symptoms improved; however, she passed away one month later.\u003c/p\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003eMultiple myeloma (MM) is a malignant clonal disorder of plasma cells, often accompanied by excessive production of immunoglobulin heavy or light chains. Its clinical manifestations typically include renal failure, hypercalcemia, symptomatic anemia, and osteolytic bone lesions. TMA and MM can present with overlapping clinical features, complicating diagnosis, especially since TMA may involve multiple organ systems beyond hematologic abnormalities. The kidney is the most frequently involved organ after the hematological system. Manifestations such as elevated creatinine, proteinuria, oliguria, and hypertension may suggest renal involvement in TMA[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Importantly, newly developed proteinuria and worsening hypertension—especially when unexplained by other causes—should prompt consideration of TMA. However, as these features are also common in MM itself, their diagnostic value is limited without further supporting evidence.\u003c/p\u003e\u003cp\u003eSeveral reports have described PI-related TMA affecting diverse organ systems. For instance, Leung et al. found that among 11 patients with confirmed PI-related TMA, three exhibited central nervous system symptoms and six had gastrointestinal involvement[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In our study, one patient experienced severe abdominal pain and bloody stools, potentially attributable to TMA-related intestinal ischemia. Though pulmonary involvement in TMA is rare, cases of pulmonary arterial hypertension and hypoxia have been reported[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our cohort, pleural effusion and multiple serous cavity effusions further supported the diagnosis. While extra-renal manifestations are non-specific, their presence during PI therapy should raise suspicion for TMA.\u003c/p\u003e\u003cp\u003eIn the first case, the patient initially presented with significant renal impairment; however, her daily urine output at admission was stable at approximately 1500–2000 mL. Over the subsequent two weeks, her renal function deteriorated progressively, yet platelet and hemoglobin levels remained at baseline, initially attributed to disease progression. Renal impairment is a common complication in MM, affecting approximately 20%-50% of patients either at diagnosis or during disease progression. Half of these cases are reversible, while around 2%-12% require renal replacement therapy[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The patient's continuous rise in creatinine and decline in urine output prompted consideration of dialysis. However, concurrent thrombocytopenia and hypertension raised further diagnostic concerns. Although bortezomib may cause thrombocytopenia, typically it is mild. Additional symptoms such as severe abdominal pain, bloody stools, elevated D-dimer levels, and inconsistent clinical and imaging findings led to the diagnosis of ischemic bowel disease, ultimately contributing to the suspicion of TMA.\u003c/p\u003e\u003cp\u003eIn the second case, hypertension and neurological symptoms following carfilzomib administration, combined with the presence of fragmented red blood cells, significantly heightened the suspicion of TMA. Thrombocytopenia, renal dysfunction, and thrombosis are critical indicators of TMA, further supported by increased schistocytes in peripheral blood. The patient developed TMA in the absence of active infection and in the context of disease remission, strongly implicating drug-induced TMA. Additionally, the patient had no prior exposure to known TMA-inducing drugs, and the temporal correlation between clinical deterioration and proteasome inhibitor use was evident.\u003c/p\u003e\u003cp\u003ePI-related TMA is clinically rare but carries substantial mortality and morbidity risks, including the potential need for long-term renal replacement therapy. Thus, early identification and effective management are critical for minimizing irreversible organ damage. Immediate cessation of the implicated drug is essential upon diagnosis. Drug rechallenge can lead to TMA recurrence, confirming its causative role, and thus should generally be avoided to prevent recurrent episodes.\u003c/p\u003e\u003cp\u003eEculizumab, a monoclonal antibody approved for the treatment of atypical hemolytic uremic syndrome, has also been used in the management of PI-related TMA in four reported cases, with two achieving clinical cure. Literature suggests that approximately 14.9% of PI-related TMA cases result in adverse outcomes[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Emerging data increasingly link complement system abnormalities, particularly in patients with mutations in complement regulatory genes, to carfilzomib-induced TMA. Therefore, such patients should be considered high-risk. Testing for the complement complex component Sc5b-9 may support the diagnosis of suspected PI-related TMA[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In cases where complement activation is suspected, early administration of eculizumab is recommended to target the underlying pathophysiology effectively[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe therapeutic benefit of therapeutic plasma exchange (TPE) remains debatable, especially in cases of carfilzomib-related TMA, where patients may derive limited benefit[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In our case, although the patient responded well to TPE, her improvement could also be attributed to the discontinuation of the causative drug. Initially, TPE was pursued out of concern for thrombotic thrombocytopenic purpura (TTP). Nonetheless, some studies suggest that TPE can improve hematologic parameters, supporting further exploration of its potential utility in managing PI-related TMA[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTMA is associated with a poor prognosis, and diagnosing PI-related TMA remains clinically challenging due to its nonspecific presentation and overlap with MM-related complications. As reports of PI-related TMA gradually increase, particularly in Western literature, clinicians in other regions, including China, should heighten their awareness of this potentially fatal complication. Currently, there are no validated predictive markers for identifying patients at risk of PI-related TMA before treatment initiation, necessitating vigilant monitoring.\u003c/p\u003e\u003cp\u003eIn summary, while no expert consensus exists on optimal treatment, both plasma exchange and eculizumab have shown promise. For patients with suspected complement activation, early administration of eculizumab may yield the best outcomes. Prompt recognition and discontinuation of the offending agent remain the cornerstone of effective management, underscoring the need for heightened clinical suspicion and a proactive therapeutic approach.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all individuals who provided support and\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eassistance in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNa Anand Can Chen analyzed the data and wrote the manuscript. Pengfei Shi \u0026nbsp;\u003c/p\u003e\n\u003cp\u003econceived the study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur institution does not require ethics approval for reporting individual cases\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eor case series.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVerbal informed consent was obtained from the patient for their information\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eand images to be published anonymously in this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMoreau P, Attal M, Facon T. 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Transfusion. 2004;44(2):294\u0026ndash;304. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1537-2995.2004.00700.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1537-2995.2004.00700.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Multiple Myeloma, proteasome inhibitor, thrombotic microangiopathy","lastPublishedDoi":"10.21203/rs.3.rs-7388047/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7388047/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eMultiple myeloma (MM) is a prevalent hematological malignancy, with proteasome inhibitors (PIs) playing a crucial role in its therapeutic management. Although PIs are generally well-tolerated and associated with relatively mild side effects, recent evidence has increasingly drawn attention to proteasome inhibitor-related thrombotic microangiopathy (PI-related TMA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation \u003c/strong\u003eHere, we report two clinical cases of PI-related TMA, highlighting the diagnostic process and subsequent management strategies. Confirmation of PI-related TMA prompted the discontinuation of the offending agent and consideration of plasma exchange therapy, which proved beneficial in selected patients. These case reports further facilitate a detailed discussion regarding the underlying pathogenic mechanisms and potential therapeutic approaches for PI-related TMA in MM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e The diagnosis of PI-related TMA in MM patients poses significant challenges due to overlapping clinical features between MM itself and TMA. The condition often presents insidiously but carries a severe prognosis, underscoring the necessity for prompt diagnosis and immediate therapeutic intervention.\u003c/p\u003e","manuscriptTitle":"Two cases of proteasome inhibitors related thrombotic microangiopathies and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-04 00:13:51","doi":"10.21203/rs.3.rs-7388047/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-27T09:26:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-17T17:23:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"228981052342993916259854466878459335247","date":"2025-09-03T02:30:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-02T21:20:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"301169549583317907832640595949230215897","date":"2025-08-28T19:16:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-27T12:18:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-19T08:38:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-19T08:36:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2025-08-16T14:19:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0cf8163c-c6ae-4da2-b400-3f2c1b597305","owner":[],"postedDate":"September 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-19T09:08:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-04 00:13:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7388047","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7388047","identity":"rs-7388047","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}