Busulfan
Myleran · Alkylator
Conditioning-regimen TMA risk.
TMA
ModerateOpen →
Proteasome inhibitor
Ixazomib
Ninlaro · IXA
The first oral proteasome inhibitor, with rare reports of drug-induced thrombotic microangiopathy.
ModerateOral proteasome inhibitor · approved 2015
Multiple myeloma (relapsed/refractory)
Signature kidney injury
Thrombotic Microangiopathy
Drug-induced thrombotic microangiopathy (TMA) is a rare, case-level event for ixazomib and is not reliably quantified. In a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS, 2004-2023), proteasome inhibitors as a class were significantly associated with TMA (213 cases; ROR 1.71), but carfilzomib accounted for the overwhelming majority of the signal (58.7% of cases; ROR ~18), with bortezomib and ixazomib contributing far fewer reports. The ixazomib signal is therefore extrapolated largely from the class.
Source: Deng et al., Support Care Cancer 2025 (FAERS pharmacovigilance)
Mechanism of kidney injury
Proteasome inhibition injures glomerular and microvascular endothelium, reducing endothelial production of protective factors (including VEGF and complement-regulatory proteins) and provoking platelet aggregation, microthrombi, and mechanical (microangiopathic) hemolysis. In the pooled PI-TMA literature, the median time to onset was about 8 days and most patients presented with the classic triad of hemolytic anemia (98%), thrombocytopenia (97%), and AKI (97%). Ixazomib TMA has been reported both as cumulative dose-dependent toxicity and via an immune-mediated mechanism; complement activation has been implicated, mirroring carfilzomib cases that responded to eculizumab.
Clinical presentation
Microangiopathic hemolytic anemia (schistocytes on smear, elevated LDH, undetectable haptoglobin, negative direct Coombs), thrombocytopenia, and AKI with rising creatinine, often with new or worsening hypertension. Gastrointestinal symptoms, fever, and fatigue frequently precede the laboratory triad.
Onset
Variable; reported after weeks to months of therapy, including with cumulative exposure. Class median time to TMA onset ~8 days from a triggering cycle.
Reversibility
Partially reversible
Anticancer mechanism
Reversibly inhibits the chymotrypsin-like activity of the 20S proteasome (beta-5 subunit), causing accumulation of polyubiquitinated misfolded proteins, ER stress, and NF-kB-dependent apoptosis in malignant plasma cells. Used orally with lenalidomide and dexamethasone for relapsed/refractory multiple myeloma.
Management
Discontinue ixazomib promptly when TMA is suspected; provide supportive care, transfusion as needed, and AKI management including dialysis when indicated (used in ~32% of pooled PI-TMA cases). TMA often improves after drug withdrawal (hematologic recovery ~96%, renal recovery ~93% in the pooled series). Plasma exchange has uncertain benefit in drug-induced TMA and is reserved for diagnostic uncertainty (suspected TTP); complement blockade with eculizumab has stabilized renal function in refractory proteasome-inhibitor TMA and can be considered.
Risk factors
- Prior or concurrent proteasome inhibitor exposure (especially carfilzomib)
- Cumulative drug exposure
- Underlying multiple myeloma with paraprotein burden
- Pre-existing endothelial/renal compromise
Prevention
- Monitor CBC, LDH, haptoglobin, and creatinine each cycle
- Maintain a low threshold to evaluate for TMA when cytopenias and AKI co-occur
- Send ADAMTS13 to exclude TTP when the triad appears
Note · TMA with ixazomib is rare and case-level; incidence is not reliably quantified. The signal is extrapolated from the proteasome-inhibitor class, where carfilzomib dominates.
Clinical depth
Renal dose adjustment
No starting-dose change for mild renal impairment (CrCl >=30). For severe renal impairment (CrCl <30) or ESRD requiring dialysis, reduce the ixazomib dose from 4 mg to 3 mg. Hepatic impairment also requires reduction.
Dialyzability & ESKD dosing
Ixazomib is not dialyzable to a clinically meaningful degree (highly protein-bound, large volume of distribution); it may be given without regard to dialysis timing. Use the reduced 3 mg dose in dialysis-dependent patients.
Differential diagnosis
Distinguish drug-induced TMA from myeloma-related causes of AKI (cast nephropathy, hypercalcemia, paraprotein-associated TMA) and from TTP (check ADAMTS13) and atypical HUS (complement). The temporal link to PI dosing, normal ADAMTS13, and improvement on drug withdrawal favor PI-TMA.
Monitoring
- CBC with smear review each cycle (platelets, schistocytes)
- LDH and haptoglobin if cytopenias develop
- Serum creatinine each cycle
- Blood pressure at each visit
Key trials & series
- TOURMALINE-MM1 (phase 3 ixazomib-Rd vs placebo-Rd in relapsed/refractory myeloma)
- FAERS proteasome-inhibitor TMA pharmacovigilance analysis (Deng et al. 2025)
Clinical pearls
- Carfilzomib carries by far the largest proteasome-inhibitor TMA signal; ixazomib reports are rare and the risk is largely class-extrapolated.
- Look for the MAHA triad: schistocytes, undetectable haptoglobin, and thrombocytopenia with AKI.
- Eculizumab has rescued renal function in refractory PI-TMA, supporting a complement-mediated component.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Glomerulus
Filtration barrier (podocytes + endothelium)
Injury signatures
Thrombotic Microangiopathy
Beyond the kidney
Class-level context for the major non-renal toxicities of proteasome inhibitors.
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- Peripheral neuropathy (bortezomib)
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- Heart failure / hypertension (carfilzomib)
Hematologic
Cytopenias, thrombosis, TMA
- Thrombocytopenia
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkIxazomib-induced thrombotic microangiopathy.Yui JC et al. · Am J Hematol 2017 · PMID 28133842First report of ixazomib-associated TMA.PMIDDrug-Induced Thrombotic Microangiopathy due to Cumulative Toxicity of Ixazomib.Atallah-Yunes SA et al. · Case Rep Hematol 2018 · PMID 30057831Case of cumulative dose-dependent ixazomib TMA with class context.PMIDProteasome inhibitor-associated thrombotic microangiopathy: a real-world retrospective and pharmacovigilance database analysis.Deng Z et al. · Support Care Cancer 2025 · PMID 39939437FAERS analysis quantifying PI-TMA risk; carfilzomib dominates, with ~8-day median onset and the MAHA/AKI triad.PMIDSimultaneous Cases of Carfilzomib-Induced Thrombotic Microangiopathy in 2 Patients With Multiple Myeloma.Myall NJ et al. · Fed Pract 2022 · PMID 36426106Class case series in which eculizumab stabilized renal function, supporting a complement-mediated mechanism.PMIDFinal Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma.Richardson PG et al. · J Clin Oncol 2021 · PMID 34111952Registrational trial establishing ixazomib-Rd; the safety dataset underpinning the agent.PMIDOnconephrology: mitigation of renal injury in chemotherapy administration.Selamet U et al. · Curr Opin Nephrol Hypertens 2024 · PMID 38095483Onconephrology review including chemotherapy-triggered thrombotic microangiopathies.
Related agents
Other agents sharing the same signature kidney injury.