Two Случаи протеазонных ингибиторов связаны с тромботическими микроангиопатиями и анализом литературы.

Introduction

Multiple myeloma (MM) is a common hematologic malignancy of older adults. Despite therapeutic advances, MM remains incurable, the adoption of novel agents has increased the 5-year survival rate to approximately 52.2% [ 1 ]. However, multidrug regimens predispose patients to adverse drug reactions. Thrombotic microangiopathy (TMA) is an endothelial injury syndrome with activation of coagulation, leading to thrombocytopenia, microangiopathic hemolytic anemia, and predominantly renal dysfunction [ 2 ]. Drug induced TMA (DITMA) is rare but can cause rapid deterioration of renal function [ 2 , 3 ]. Although proteasome inhibitors (PIs) were not traditionally linked to TMA, accumulating evidence now implicates them in select cases [ 3 , 4 ]. Distinguishing the cause of severe thrombocytopenia and kidney injury in MM is therefore challenging. Here, two cases with high clinical suspicion for PI-related TMA and outline the clinical features, potential 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-κ 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 360 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. Inflammatory markers were elevated but non-specific, blood cultures and imaging were negative, and there was no clinical focus of infection, sepsis could not be completely ruled out but was considered unlikely based on the totality of data. Coagulation parameters, including fibrinogen and D-dimer, did not fulfill classical criteria for overt disseminated intravascular coagulation (DIC), and the overall pattern of thrombocytopenia with microangiopathic hemolytic anemia favored TMA rather than DIC as the primary process. Furthermore, due to the negative results for antiphospholipid antibodies and the absence of arteriovenous thrombosis, antiphospholipid antibody syndrome was excluded. The activity of ADAMTS13, measured using a fluorescence resonance energy transfer (FRET) assay, was 81% (reference range 70–120%), which does not support a diagnosis of immune thrombotic thrombocytopenic purpura (TTP). The direct antiglobulin test (DAT) was negative, arguing against autoimmune hemolytic anemia. Haptoglobin was 0.93 g/L (reference range 0.30–2.00 g/L) on March 28, which did not support prominent intravascular hemolysis at that time.

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 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 and deterioration of laboratory data closely matched the median onset time for PI drug-induced TMA (Table 1 ). This strong temporal association suggested that the PI medications were likely responsible for the patient’s TMA.

Fig. 1 The course of clinical and laboratory changes in case1

Table 1 Time of medication and laboratory data in case1 2.27& 3.1 3.4 3.5& 3.6 3.7 3.14 3.15& 3.16 3.18 3.20& 3.21 3.24 3.25 3.26# 3.28 MBP(90–139/60–89) mmHg 142/82 138/71 131/79 147/89 147/86 156/95 145/84 149/99 140/95 152/91 147/91 134/89 160/102 179/89 149/90 133/81 Hb(115–150)g/L 59 73* 59* 84 71 67 88* 82 78 69* 71 66* 68* 65 65 51 Plt(125–350) 10 9 /L 73 70 74 97 83 76 52 55 40 22 37 38 21 39 39 63 Ret (0.5–1.5)% 0.56 0.38 0.59 NA 0.48 0.40 0.56 0.52 0.66 1.02 0.56 0.78 0.76 1.04 1.04 1.19 LDH (120–250)U/L 282 227 256 267 232 242 456 464 430 424 499 437 501 353 353 330 Cr (41–81)µmol/L 217 207 360 360 356 321 434 460 403 444 386 306 415 397 397 508 eGFR(90–120)mL/min/1.73 m² 22.26 23.82 12.26 12.26 12.38 14.07 9.80 9.14 10.71 9.73 11.28 14.90 10.34 10.90 10.90 8.51 TBIL( ≦ 26)µmol/L 3.1 6.5 4.9 8.8 3.2 3.6 13.5 13.0 13.0 15.7 23.0 17.1 19.7 30.2 16.9 9.7 UCB(1.0-20.1)µmol/L 2.1 4.3 1.7 6.6 1.8 2.3 9.0 8.5 8.4 10.1 15.7 11.6 14.1 21.0 12.1 6.0 PT(9.2–13.9) sec 13.2 13.7 15.8 12.9 13.7 13.7 17.2 18.5 20.3 16.2 15.0 16.0 14.2 14.6 14.6 15.4 APTT(21.2–34.8) sec 27.0 29.0 35.4 30.0 33.7 31.4 35.9 37.7 39.9 34.0 32.3 37.1 32.3 28.8 28.8 31.7 Fg(2–4)g/L 2.60 3.13 4.12 5.13 3.59 3.51 5.0 5.07 4.90 3.87 3.86 4.5 3.10 2.98 2.98 1.96 D-D(0-550) µg/L 1040 1540 1470 2090 1470 2160 2790 3300 6180 10,200 5990 3480 15,980 20,310 20,310 10,180 Haptoglobin(0.30-2.00)g/L NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 0.93 DAT NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA negative MBP:maximal blood pressure; Hb: hemoglobin; Plt: platelet; Ret:reticulated corpuscles; LDH:lactate dehydrogenase; Cr:creatinine; eGFR: estimated glomerular filtration rate TBIL:total bilirubin; UCB:unconjugated bilirubin; PT:prothrombin time; APTT:partial prothrombin time;Fg:fibrinogen;D-D: D-dimer; DAT: direct antiglobulin test; NA:not available * after red cells transfusion; # plasma exchange;& Bortezomib

Therapeutic plasma exchange (TPE) was initiated emergently at the time TMA/immune TTP was first suspected and resulted in rapid improvement in clinical symptoms, urine output, blood pressure, and platelet counts. After ADAMTS13 activity returned within the normal range and complement testing became available, soluble C5b-9 levels were found to be elevated in a pattern consistent with complement activation (Table 2 ), supporting a diagnosis of complement mediated TMA. A total of 11 TPE sessions were administered after proteasome inhibitor therapy was permanently discontinued. Eculizumab was considered but ultimately not used because of financial constraints and the patient’s favorable response to TPE. Renal function and platelet counts subsequently stabilized, with complement levels normalizing by May 2023. Chemotherapy was adjusted to daratumumab plus dexamethasone, and no TMA recurrence was observed during follow up.

Table 2 Sc5b-9 level after plasma exchange in case1 TPE frequency Sample timing Result (ng/ml) Reference ranges (ng/ml) 4 4.15 460.0 72–345 6 4.27 460.8 72–345 10 5.20 300.8 72–345 TPE: therapeutic plasma exchange

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 on March 13. Soon after initiation, she experienced severe hypertension (peak 191/114 mmHg) and severe headaches responsive only temporarily to antihypertensive treatments. The laboratory dates after treatment were shown in Table 3 ; Fig. 2 .

Fig. 2 The course of clinical and laboratory changes in case 2

Table 3 Time of medication and laboratory data in case 2 3.11 3.14& 3.15 3.16 3.17 3.18 MBP(90–139/60–89) mmHg 123/85 141/71 169/92 172/87 191/114 126/70 Hb(115–150 g/L) 101 84 NA NA 98 85 Plt(125–350) 10 9 /L 15 7 NA NA 40* 17 Ret (0.5–1.5)% 1.14 1.46 NA NA 0.37 1.4 LDH (120–250)U/L 205 363 NA NA 199 155 Cr (41–81)µmol/L 47 42 NA NA 44 44 eGFR(90–120)mL/min/1.73 m² 95.12 97.73 NA NA 96.64 96.64 TBIL( ≦ 26)µmol/L 16.2 9.0 NA NA 11.7 14.6 UCB(1.0-20.1µmol/L 8.6 4.3 NA NA 7.1 7.1 PT(9.2–13.9) sec 12.2 11.1 NA NA 11.6 14.1 APTT(21.2–34.8) sec 34.8 34.0 NA NA 25.6 36.5 Fg(2–4)g/L 1.87 1.64 NA NA 2.51 3.92 D-D (0-550) µg/L 870 2959 NA NA 2815 6875 Haptoglobin(0.30-2.00)g/L NA NA NA NA NA NA DAT NA NA NA NA NA NA MBP: maximal blood pressure; Hb: hemoglobin; Plt: platelet; Ret: reticulated corpuscles; LDH: lactate dehydrogenase; Cr: creatinine; eGFR: estimated glomerular filtration rate; TBIL: total bilirubin; UCB: unconjugated bilirubin; PT: prothrombin time; APTT: partial prothrombin time; Fg: fibrinogen; D-D: D-dimer; DAT: direct antiglobulin test; NA: not available; *after platelet transfusion, platelet-raising drugs; & Carfilzomib

On day four after discontinuation of carfilzomib, the patient developed uncontrollable limb convulsions lasting nearly two hours that were resistant to initial antiepileptic therapy. A bedside neurologic examination was performed, and emergent non-contrast head CT ruled out intracranial hemorrhage, acute cerebral infarction, and space-occupying lesions. Brain MRI, the preferred modality for detecting posterior reversible encephalopathy syndrome (PRES), was not obtained because of the patient’s rapid clinical deterioration and subsequent request for early discharge. As a result, PRES could not be definitively confirmed or excluded, which represents an important limitation of this case.

Laboratory investigations at the time of neurologic deterioration showed elevated inflammatory markers, anemia, thrombocytopenia, mild schistocytosis (3%), and normal fibrinogen levels, findings that did not support overt disseminated intravascular coagulation (DIC). The absence of a diarrheal prodrome made typical Shiga toxin-mediated hemolytic uremic syndrome (HUS) unlikely. On site ADAMTS13 activity testing and extended complement studies were not available on an emergent basis at our institution, as these assays are processed at a regional reference laboratory with a multi-day turnaround time and are not accessible during off hours. Haptoglobin and direct antiglobulin test (DAT) were not available because of early discharge and incomplete hemolysis work-up. Immune TTP was considered less likely in view of the close temporal relationship to carfilzomib initiation, the presence of malignant hypertension with acute neurologic symptoms, normal fibrinogen and coagulation parameters, and a clinical manifestation highly suspected PI-associated TMA. Given the low pretest probability of immune TTP, empiric plasma exchange was not initiated. The patient elected to discontinue chemotherapy and was discharged at her own request. Post-discharge, her seizure symptoms improved; however, she declined further diagnostic evaluation, and she died approximately one month later.

Discussion and conclusions

PI-associated TMA is an uncommon but potentially life-threatening complication in multiple myeloma (MM). Because MM and its therapies can also cause anemia, thrombocytopenia, renal dysfunction, and hypertension, PI-TMA may be under-recognized. In practice, newly developed or rapidly worsening hypertension, proteinuria, or renal dysfunction together with thrombocytopenia and microangiopathic hemolysis, especially when temporally related to proteasome inhibitor exposure should prompt consideration of TMA [ 2 , 5 ]. Although the kidney is the most frequently affected solid organ, extra-renal manifestations can occur and may dominate the clinical presentation [ 6 ]. Because kidney biopsy may not be practical in unstable, thrombocytopenic patients, diagnosis frequently remains clinical and should be interpreted in the context of temporal association and systematic exclusion of alternative causes.

Emerging data support a VEGF-complement axis in PI-TMA. In MM, VEGF sustains endothelial VEGFR2 signaling and may promote complement regulation (e.g., via factor H), thereby restraining alternative pathway amplification [ 7 , 8 ]. Proteasome inhibition can suppress NF-κB/VEGF-related signaling and weaken endothelial protection, facilitating alternative pathway activation [ 9 – 11 ]. Complement involvement has been reported, including C5b-9 deposition and elevations of soluble C5b-9 that may track disease activity; clinical improvement with terminal complement blockade has been documented in selected cases [ 12 – 15 ]. Genetic susceptibility also appears relevant, including enrichment of CFHR3-CFHR1 or CFHR1-CFHR4 deletions among carfilzomib-treated patients who developed TMA, consistent with background dysregulation of the alternative pathway [ 16 ]. Collectively, these findings support a model in which proteasome inhibitor exposure reduces VEGF-dependent endothelial protection and unmasks complement dysregulation in predisposed individuals. Measurement of soluble C5b-9 may assist diagnosis and inform consideration of complement-directed therapy in addition to drug withdrawal.

PI-TMA is heterogeneous and may involve extra-renal organs [ 6 ]. Prior cohorts have described central nervous system and gastrointestinal involvement, illustrating a broad clinical spectrum [ 6 ]. Our cases align with this pattern: Case 1 developed severe abdominal pain and hematochezia compatible with intestinal ischemia, whereas Case 2 exhibited seizures with malignant hypertension. A clear temporal association was evident in both patients, Case 1 progressed subacutely with exacerbations tracking each bortezomib exposure (Fig. 1 ; Table 1 ), whereas Case 2 deteriorated within the first week of carfilzomib therapy, consistent with prior series [ 6 ]. Baseline clinical context created distinct diagnostic challenges: in Case 1, renal injury was initially attributed to MM-related mechanisms, while in Case 2, profound baseline thrombocytopenia and heavy pretreatment obscured recognition of superimposed TMA-pitfalls also noted in prior reports [ 6 ].

Both patients underwent evaluation for alternative causes of TMA, including infection/sepsis, disseminated intravascular coagulation (DIC), antiphospholipid syndrome, disseminated malignancy, and primary thrombotic disorders. Neither patient had a clear infectious focus, serial blood cultures were negative and imaging did not identify infection, so sepsis could not be completely ruled out but was considered unlikely based on the totality of data. Coagulation parameters did not support overt DIC as the primary process, and antiphospholipid antibody testing was negative. Hematologic findings were compatible with microangiopathic hemolysis, with schistocytes identified in both cases (2% and 3%, respectively). In Case 1, ADAMTS13 activity was within the normal range, arguing against immune thrombotic thrombocytopenic purpura (TTP). In Case 2, emergent ADAMTS13/complement assays and brain MRI were not available, which increases diagnostic uncertainty; accordingly, this case is best described using cautious terminology (probable/highly suspected PI-TMA). Overall, these observations are consistent with reports that chemotherapy-associated TMA generally lacks severe ADAMTS13 deficiency [ 6 ].

Across reports, the most consistent management principle is immediate discontinuation of the suspected PI at the earliest clinical suspicion of PI-TMA, together with prompt supportive care, especially blood pressure control and organ support [ 6 , 12 , 17 ]. Published series report adverse outcomes in a meaningful minority of patients (approximately 15%), underscoring the need for early recognition and individualized escalation [ 3 , 6 , 14 , 18 ]. In our systematic review of 115 cases, unrecognized early TMA-like abnormalities during earlier treatment cycles were occasionally followed by continued PI exposure and subsequent progression to overt TMA, including fatal outcomes [ 12 ]. These observations support close monitoring of blood pressure, renal function, and hemolysis markers during PI therapy.

The role of plasma exchange remains uncertain. Plasma exchange is reasonable when immune TTP cannot be confidently excluded and may improve hematologic parameters in selected patients, but benefit in chemotherapy-associated or complement-mediated TMA is inconsistent; moreover, it can complicate subsequent complement inhibition by increasing eculizumab clearance [ 11 , 19 , 20 ]. Eculizumab provides a mechanistically targeted option when complement activation is suspected or when there is inadequate response to PI withdrawal with or without plasma exchange. Accumulating reports suggest that eculizumab may be particularly beneficial in PI-TMA, including some carfilzomib-associated cases with poor response to plasma exchange [ 12 , 19 ]. Practical limitations include access and cost, meningococcal vaccination and infection vigilance, and supplemental dosing if plasma exchange is performed.

Our outcomes illustrate both potential recovery and fulminant progression. Case 1 improved rapidly after bortezomib withdrawal and therapeutic plasma exchange and remained stable after switching to daratumumab plus dexamethasone, eculizumab was not used because of financial constraints and favorable response. In contrast, Case 2 declined definitive inpatient therapy and died within one month, highlighting the potentially fulminant course of carfilzomib-associated PI-TMA and reinforcing the importance of early recognition and intervention [ 6 , 12 , 17 ].

We evaluated concomitant medications using WHO-UMC criteria and the Naranjo algorithm (Tables S1 , S2 ). In both cases, the proteasome inhibitors obtained the highest causality scores, supporting a probable association, however, deliberate re-exposure was avoided, and a true negative re-exposure to non-PI agents could only be documented in Case 1. Additional limitations include the absence of kidney biopsy in both cases, delayed timing of soluble C5b-9 sampling in Case 1 (after multiple plasma exchanges), and incomplete diagnostic evaluation in Case 2 due to early discharge. Despite these constraints, the convergence of clinical features, laboratory findings, temporal relationships to PI exposure, and de-challenge information supports PI-associated, likely complement-mediated TMA.

In conclusion, prompt recognition and discontinuation of the suspected PI are fundamental, and plasma exchange and/or eculizumab may be considered in selected patients based on diagnostic uncertainty, evidence of complement activation, and clinical severity.

Supplementary Information

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Supplementary Material 1

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Acknowledgements

The authors would like to thank all individuals who provided support and assistance in this study.

Author contributions

Na An and 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.

Data availability

No datasets were generated or analysed during the current study.

Declarations

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.

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