Genetic and Functional Evidence of Complement Dysregulation in Multiple Myeloma Patients with Carfilzomib-Induced Thrombotic Microangiopathy Compared to Controls

Gavriilaki, Eleni; Dalampira, Dimitra; Theodorakakou, Foteini; Liacos, Christine‐Ivy; Kanellias, Nikolaos; Eleutherakis‐Papaiakovou, Evangelos; Terpos, Evangelos; Gavriatopoulou, Maria; Verrou, Evgenia; Triantafyllou, Theodora; Sevastoudi, Aggeliki; Koravou, Evaggelia-Evdoxia; Touloumenidou, Tasoula; Varelas, Christos; Papalexandri, Apostolia; Sakellari, Ioanna; Dimopoulos, Meletios Α.; Kastritis, Efstathios; Katodritou, Eirini

doi:10.3390/jcm11123355

Cited by 9 publications

(9 citation statements)

References 39 publications

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“…They showed that complement-related variants were more common in patients with carfilzomib-induced TMA than in non-TMA controls, regardless of patient and treatment characteristics. ADAMTS13 activity was reduced and C5b-9 levels were elevated compatible with the phenotype of complement-related TMA [8].…”

Section: Discussionmentioning

confidence: 88%

“…A recent study recruited consecutive patients with carfilzomib-induced TMA and compared them with patients receiving carfilzomib treatment without TMA [8]. The authors analyzed genomic DNA from peripheral blood using next generation sequencing (NGS) with a complement-related gene panel: ADAMTS13 activity and soluble C5b-9.…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have shown that immediate discontinuation of carfilzomib plus supportive care may be sufficient to improve the manifestations of the disease. There is limited evidence that eculizumab, a monoclonal antibody against the complement protein C5, could be beneficial in patients with carfilzomib-induced TMA [3,[6][7][8]. The involvement of activation of the alternative pathway of the complement is an argument for the use of eculizumab in carfilzomib-induced TMA.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study recruited consecutive patients with carfilzomib-induced TMA and compared them with patients receiving carfilzomib treatment without TMA. 8 The authors analyzed genomic DNA from peripheral blood using next generation sequencing with a complement-related gene panel as follows: ADAMTS13 activity and soluble C5b9. They showed that complement-related variants were more common in patients with carfilzomib-induced TMA than in non-TMA controls, regardless of patient and treatment characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…Etiological analyses comprised negative results of stool cultures (polymerase chain reactionbased detection assay for shiga-toxin), of hepatitis and human immunodeficiency virus serologies, of antinuclear and antiphospholipid antibodies tests, and normal values of ADAMTS-13 activity (104%). The results of the plasma assessment of the alternative complement pathway were as followed: the complement factor proteins were in normal range values (CH50 96 %, C3 899 mg/L, C4 257 mg/L, factor H 99 %, factor I 83 %), the expression of CD46 was reduced (8,2) and the level of sC5b9 was elevated (571 ng/ml).…”

Section: Case Presentationmentioning

confidence: 99%

See 4 more Smart Citations

Carfilzomib Induced Microangiopathy due to Accumulation With Paxlovid

Philipponnet

Aniort²,

Atenza³

et al. 2022

Kidney International Reports

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Case Presentationmentioning

confidence: 99%

See 3 more Smart Citations

Carfilzomib Induced Microangiopathy due to Accumulation With Paxlovid

Philipponnet

Aniort²,

Atenza³

et al. 2022

Kidney International Reports

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Complement biology for hematologists

Duval

Frémeaux‐Bacchi

2023

American J Hematol

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The complement system is part of the innate immunity. An increased activation or a loss of the regulation of this fine-tuned cascade is involved in a variety of hematological diseases. During the last decade, anti-C5 therapies have revolutionized the management and prognosis of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic and uremic syndrome (aHUS). The availability of a rapidly growing number of innovative complement inhibitors has opened new therapeutic perspectives for several other hematological disorders in which the complement is involved at different degrees. This review focuses on complement biology and its mechanisms of activation in hematological diseases.Recently, the first demonstration of the efficacy of C1s inhibition efficiency in cold agglutin disease (CAD) has provided an illustration of these new targets within the complement cascade for the treatment of hematological disorders.

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Carfilzomib‐Induced Thrombotic Microangiopathy—Two Case Reports

Attucci,

Pilerci,

Messeri

et al. 2024

Cancer Reports

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BackgroundThrombotic microangiopathy (TMA) is a pathological syndrome characterized by a combination of three key features: microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ damage, primarily affecting the kidneys. There are several drugs known to have a definite or probable causal association with TMA, and carfilzomib, a second‐generation irreversible proteasome inhibitor (PI), approved for the treatment of multiple myeloma (MM), is one of them. In the medical literature, there have been a growing number of reports describing this serious adverse event occurring in MM patients. The precise mechanisms underlying the development of PI‐induced TMA are not yet fully understood. Significant improvements in both renal and hematological aspects have been documented following the administration of eculizumab.Recent FindingsIn this report, we present two cases of MM patients who developed TMA while undergoing carfilzomib therapy. These cases were successfully treated at the Haematology Unit, Careggi Hospital in Florence. In our cases as well, the introduction of eculizumab resulted in rapid enhancements in renal function and platelet count, ultimately leading to the discontinuation of hemodialysis after 4 and 2 weeks, respectively.Discussion and ConclusionWe assessed 91 patients who received carfilzomib‐based therapies at our Haematology Department, during which we identified two cases of DITMA (2.2% incidence). Additionally, we conducted a literature review and discovered a total of 75 documented cases of carfilzomib‐induced TMA. Our experience aligns with the cases reported in literature: this adverse event can manifest at any point during treatment, regardless of the specific drug combinations used alongside carfilzomib. The initial and most crucial step in its management involves discontinuing carfilzomib therapy; therefore, recognizing TMA in a timely manner is of utmost importance. Eculizumab could play a role in improving and expediting the resolution of this potentially fatal adverse event, but further studies are needed.In a MM patient receiving carfilzomib, presenting with anemia, thrombocytopenia, and impaired renal function, a carfilzomib‐induced TMA should be suspected in order to discontinue the causative agent.

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Genetic and Functional Evidence of Complement Dysregulation in Multiple Myeloma Patients with Carfilzomib-Induced Thrombotic Microangiopathy Compared to Controls

Cited by 9 publications

References 39 publications

Carfilzomib Induced Microangiopathy due to Accumulation With Paxlovid

Carfilzomib Induced Microangiopathy due to Accumulation With Paxlovid

Complement biology for hematologists

Carfilzomib‐Induced Thrombotic Microangiopathy—Two Case Reports

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