Busulfan
Myleran · Alkylator
Conditioning-regimen TMA risk.
TMA
ModerateOpen →
Proteasome inhibitor
Carfilzomib
Kyprolis · Carfil
The proteasome inhibitor with a real renal signature — common AKI, thrombotic microangiopathy and hypertension in myeloma.
SevereProteasome inhibitor (second generation) · approved 2012
Multiple myeloma
Signature kidney injury
Thrombotic Microangiopathy
Representative incidence17%
Renal complications are common and a recognized class concern: in a 114-patient real-world cohort, ~17% had carfilzomib-attributable renal events (TMA ~5%, albuminuria >1 g/day ~6%, otherwise-unexplained grade >=3 AKI ~5%), occurring mostly early and unpredictably. On the prospective CARDAMON trial, TMA occurred at ~1.6-4.2 events per 1,000 patient-cycles, with most patients hypertensive and almost all developing AKI. Pharmacovigilance (FAERS) shows carfilzomib carries by far the strongest TMA signal among proteasome inhibitors.
Source: Fotiou et al., Blood Cancer J 2020 (114-patient cohort)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeveritySevere
ReversibilityPartially reversible
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Thrombotic Microangiopathy
Endothelial injury with microvascular thrombi, hemolysis and thrombocytopenia — gemcitabine, mitomycin C, anti-VEGF.
Mechanism of kidney injury
Endothelial injury — likely from proteasome-inhibition-induced loss of endothelial homeostasis and a complement-amplified response — drives a thrombotic microangiopathy with microvascular thrombosis, microangiopathic hemolysis, thrombocytopenia and AKI; renal biopsy in the cohort showed FSGS in some albuminuric patients, implicating a shared endothelial/podocyte mechanism. Carfilzomib also causes hypertension that compounds renal risk, and underlying myeloma kidney disease frequently coexists. Direct tubular (ATN) injury can also occur.
Clinical presentation
AKI with new or worsening hypertension; in TMA, microangiopathic hemolytic anemia (schistocytes, elevated LDH, low haptoglobin), thrombocytopenia and rising creatinine, sometimes requiring dialysis; in the podocytopathy variant, new albuminuria/proteinuria with relatively preserved or modestly reduced GFR. Onset is often abrupt, within the first cycles.
Onset
Variable — frequently early (first cycles), but TMA can also appear later, sometimes after a treatment break and re-escalation.
Reversibility
Partially reversible
Anticancer mechanism
Irreversible (epoxyketone) inhibitor of the chymotrypsin-like activity of the 20S proteasome, causing accumulation of misfolded/ubiquitinated proteins, ER stress and apoptosis in myeloma cells. Used in relapsed/refractory multiple myeloma.
Management
Hold/discontinue carfilzomib at first suspicion of TMA; supportive AKI care and aggressive hypertension control; plasma exchange and complement inhibition (e.g., eculizumab) have been used successfully in reported carfilzomib-TMA cases; dialysis if severe. Across the PI-TMA literature, drug cessation plus supportive care (with PLEX/HD/eculizumab as needed) achieved hematologic and renal recovery in the large majority.
Risk factors
- Pre-existing or treatment-emergent hypertension
- Underlying myeloma renal disease
- Volume status changes
- Re-escalation after treatment breaks
- Prior endothelial injury (e.g., post-transplant)
Prevention
- Aggressive blood-pressure control before and during therapy
- Step-up dosing with dexamethasone premedication and adequate hydration on initiation/re-escalation
- Baseline and on-treatment monitoring of renal function, CBC, LDH, haptoglobin and urine protein
Note · Carfilzomib has the strongest renal signature of the proteasome inhibitors. TMA is the headline serious lesion; AKI, albuminuria/FSGS and hypertension are individually common. Reported TMA-rate figures are trial-specific.
Clinical depth
Renal dose adjustment
Per label no starting-dose adjustment is required across renal function including dialysis (carfilzomib is rapidly metabolized by peptidase/epoxide hydrolase, not renally cleared); however, given the high rate of renal events, monitor closely and hold for TMA/AKI rather than adjusting prophylactically.
Dialyzability & ESKD dosing
On hemodialysis days, administer carfilzomib after the HD session (per label) because of theoretical dialytic clearance considerations; the parent drug is largely cleared by non-renal metabolism. Dialysis is otherwise used to support TMA/AKI.
Differential diagnosis
Separate carfilzomib-TMA (MAHA, thrombocytopenia, schistocytes, normal ADAMTS13) from TTP (severe ADAMTS13 deficiency), from atypical HUS, and from myeloma-related kidney disease (cast nephropathy, light chains). The combination of new hypertension + AKI + hemolysis on carfilzomib is the classic trigger to stop the drug and work up TMA.
Monitoring
- Blood pressure at every visit (and home monitoring) - hypertension precedes/accompanies TMA
- CBC, LDH, haptoglobin and peripheral smear for schistocytes, especially in the first cycles and on re-escalation
- Serum creatinine and urine protein each cycle
Key trials & series
- CARDAMON (Camilleri Br J Haematol 2021; TMA rate and mitigation)
- Fotiou Blood Cancer J 2020 (114-patient renal-toxicity cohort, ~17% renal events)
- Deng Support Care Cancer 2025 (FAERS PI-TMA pharmacovigilance, carfilzomib dominant)
Clinical pearls
- Carfilzomib has the strongest renal/TMA signature of the proteasome inhibitors - new hypertension plus AKI plus hemolysis means stop the drug and check a smear and ADAMTS13.
- Renal events are common (~17% in cohort data), early and unpredictable - monitor from cycle 1.
- No renal dose adjustment is required (it is non-renally cleared), but give it after HD on dialysis days.
- Re-escalation after a treatment break is a recognized trigger for TMA.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Thrombotic MicroangiopathyAcute Tubular NecrosisHypertension
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
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkCarfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.Fotiou D et al. · Blood Cancer J 2020 · PMID 33149167Cohort: 17% carfilzomib-attributable renal events (TMA 5%, albuminuria 6%, unexplained grade >=3 AKI 5%); biopsy FSGS implicates an endothelial/podocyte mechanism.PMIDThrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study.Camilleri M et al. · Br J Haematol 2021 · PMID 33650100Prospective trial: most TMA cases hypertensive, 7/8 with AKI; TMA rate fell from 4.2 to 1.6 per 1,000 patient-cycles after mitigation.PMIDProteasome inhibitor-associated thrombotic microangiopathy: a real-world retrospective and pharmacovigilance database analysis.Deng Z et al. · Support Care Cancer 2025 · PMID 39939437FAERS analysis: carfilzomib accounts for 58.7% of PI-TMA with the highest signal (ROR ~18); median onset 8 days; AKI in 96.7%; drug cessation + PLEX/HD/eculizumab improved outcomes.PMIDMicroangiopathy in multiple myeloma: a case of carfilzomib-induced secondary thrombotic microangiopathy successfully treated with plasma exchange and complement inhibition.Catanese L et al. · BMC Nephrol 2023 · PMID 37337151Carfilzomib-induced TMA with AKI managed with plasma exchange and eculizumab.PMIDRenal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma.Hobeika L et al. · BMC Nephrol 2014 · PMID 25267524Biopsy-proven renal TMA with podocytopathy and new proteinuria/hypertension that improved after stopping carfilzomib.PMIDThrombotic microangiopathy associated with proteasome inhibitors.Lodhi A et al. · Clin Kidney J 2015 · PMID 26413293Reviews proteasome-inhibitor-associated TMA/AKI, including biopsy-proven carfilzomib TMA.PMIDAnticancer Drug-Induced Acute Kidney Injury.Izzedine H et al. · Kidney Int Rep 2017 · PMID 29318217Onconephrology reference for TMA and other vascular drug-induced injury.
Related agents
Other agents sharing the same signature kidney injury.