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Cereblon E3 ligase modulator (CELMoD)

Iberdomide

Zenbexus · IBER

Cereblon E3 ligase modulator (CELMoD) · approved 2026 · 7 references

The first approved cereblon E3 ligase modulator, whose kidney relevance runs the other way — the drug accumulates below eGFR 30 and the dose drops, while its randomized safety table shows no excess renal impairment over the comparator arm.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Mild
Reversibility
Reversible
Onset
No drug-specific renal onset window exists, because no renal lesion is attributed to the drug. Its own time-course risks are hematologic and thrombotic and accrue over the first cycles; a creatinine change follows its own precipitant - disease progression, intercurrent illness, a co-administered nephrotoxin - on that cause's timeline rather than the drug's.

Signature kidney injury & incidence

Prerenal / Hemodynamic AKI.

No renal lesion is attributed to iberdomide, and the randomized comparison is the reason that can be said plainly rather than assumed. In the FDA label's EXCALIBER-RRMM safety population, renal impairment - a composite adverse-reaction term - occurred in 11% of patients on iberdomide with daratumumab/hyaluronidase and dexamethasone (N=204) and in 8% on the daratumumab/hyaluronidase, bortezomib and dexamethasone comparator arm (N=204), with grade 3-4 rates of 3.4% and 3.9% respectively - numerically lower on the iberdomide arm. In relapsed or refractory myeloma the kidney is a target organ of the disease itself (cast nephropathy, hypercalcemia, volume depletion), so a single-arm rate of 11% would have read as drug toxicity; the comparator shows most of it belongs to the population. The label carries no renal warning, and the boxed warning is embryo-fetal toxicity and serious venous and arterial thromboembolism. Phase 3 results are not yet published, so these figures come from the label rather than from a peer-reviewed report.

Source: No drug-attributable renal incidence: renal impairment 11% all-grade / 3.4% grade 3-4 on the iberdomide arm (N=204) versus 8% / 3.9% on the DVd comparator arm (N=204), FDA label EXCALIBER-RRMM safety population

Reported injury signatures: Prerenal / Hemodynamic AKI.

Mechanism of kidney injury

No direct nephrotoxic mechanism is established. What the kidney does to iberdomide is the documented relationship, not the reverse. Roughly 46% of a radiolabelled dose is recovered in urine (16% as unchanged drug) and 43% in feces (11% unchanged), with CYP3A the primary metabolic route; normal, mild and moderate impairment leave exposure unchanged, but below eGFR 30 mL/min/1.73 m2 without dialysis total clearance falls and exposure of both iberdomide and its active metabolite M12 rises - a 1.8-fold higher AUC with comparable Cmax against healthy subjects. The class's vascular hazard is thrombotic rather than nephritic: venous thromboembolic events occurred in 6.4% and arterial events in 3.4% of the iberdomide arm despite mandatory prophylaxis, which is a renal concern only through the uncommon route of renal vein thrombosis or embolic infarction, not through a tubular or glomerular lesion.

Clinical presentation

There is no characteristic renal presentation. A creatinine rise during treatment should be worked up as myeloma kidney disease until proven otherwise - cast nephropathy from persisting free light chains, hypercalcemia, or volume depletion from diarrhea and reduced intake - rather than attributed to the drug. Because iberdomide is only ever given with daratumumab and dexamethasone, the backbone's own effects sit ahead of it on the differential. Hematuria is worth naming separately: the label counts it inside a composite hemorrhage term (10% on the iberdomide arm versus 9% on the comparator) alongside epistaxis and gastrointestinal bleeding, in a drug whose labelled toxicities include grade 4 thrombocytopenia - so red urine here is more often a platelet problem than a glomerular one.

Management

No iberdomide-specific renal management exists, because no renal lesion is attributed to it. A rising creatinine calls for a myeloma-kidney workup - serum free light chains, calcium, volume status, urinalysis with quantified protein, and imaging for obstruction - before the drug is blamed or stopped, since stopping effective myeloma therapy is itself a renal risk in a patient whose kidney disease is driven by the plasma-cell clone. If eGFR crosses below 30 without dialysis, reduce to 0.75 mg once daily rather than discontinuing. If the patient starts intermittent hemodialysis, the label directs no dose adjustment at all. Manage thromboembolism per the label: interrupt for grade 3 or higher events, anticoagulate, and restart at 0.75 mg once daily once acute symptoms have resolved.

Risk factors

  • eGFR below 30 mL/min/1.73 m2 without dialysis - the single threshold at which the label changes the dose, because exposure runs 1.8-fold higher there
  • Active myeloma with circulating free light chains: cast nephropathy is the dominant renal risk in this population and is disease, not drug
  • Concomitant strong or moderate CYP3A inhibitors, which raise exposure independently of kidney function and carry their own separate dose reduction
  • Known thromboembolism risk factors, given a boxed warning for venous and arterial events that occurred despite mandatory prophylaxis on trial
  • Volume depletion from diarrhea or reduced oral intake, common on the daratumumab and dexamethasone backbone

Prevention

  • Establish eGFR before the first dose and set the starting dose from it - 0.75 mg once daily below 30 mL/min/1.73 m2 off dialysis, 1 mg otherwise - so the exposure increase is corrected at initiation rather than after toxicity appears
  • Avoid concomitant strong or moderate CYP3A inhibitors; where use is unavoidable, take the label's reduction (1 mg every other day for strong, 0.75 mg once daily for moderate) to hold exposure in range
  • Give thromboembolism prophylaxis per myeloma practice - the registrational trial mandated it and still recorded 6.4% venous and 3.4% arterial events
  • Maintain hydration through diarrhea or reduced oral intake so prerenal physiology does not compound the disease's own renal burden
  • Treat the myeloma effectively: in this disease the most powerful thing that protects the kidney is control of the light chains driving cast nephropathy

Renal dose adjustment

The label sets exactly one renal threshold, and it has a deliberate exception in the middle of it. At eGFR below 30 mL/min/1.73 m2 NOT receiving dialysis, reduce to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle; if a further reduction is needed for adverse events, 1 mg every other day on the same schedule. At eGFR 30 or above - and also at eGFR below 30 WITH intermittent hemodialysis - no dose adjustment is recommended. Dose modifications for CYP3A inhibitors are separate and can be the more frequent trigger: strong inhibitors are to be avoided, and if unavoidable the dose drops to 1 mg every other day; moderate inhibitors drop it to 0.75 mg once daily.

Dialyzability & ESKD dosing

Partially removed, with no dose consequence. Dialysis clearance measured 3.07 L/hr, about 16% of total clearance in patients with kidney failure on intermittent hemodialysis - real but small, and total clearance and exposure on hemodialysis were comparable to subjects with normal renal function. The label therefore recommends no dose adjustment for these patients and directs no post-dialysis timing or supplemental dose, which is why dialysis patients are the one group below eGFR 30 who stay on the full 1 mg. Iberdomide is 75% plasma protein bound with a 415 L apparent volume of distribution and a 37-hour terminal half-life, which is why removal stays partial. Peritoneal dialysis and CRRT are not characterized.

Differential diagnosis

In this population the drug is rarely the answer. Myeloma itself produces most of the renal impairment that fills the adverse-event table, and the label's own comparator arm quantifies how much: 8% all-grade and 3.9% grade 3-4 without any iberdomide at all. Work the standard myeloma-kidney differential first - cast nephropathy, hypercalcemia, prerenal physiology, light-chain deposition, amyloidosis, contrast or an antimicrobial - and reach for a drug attribution only when those are excluded. The class contrast is the other trap: lenalidomide, roughly 80% renally cleared, carries genuine reports of azotemia with rare Fanconi syndrome and thrombotic microangiopathy, and none of that literature transfers to a drug cleared mainly by CYP3A.

Monitoring

  • Serum creatinine and eGFR at baseline and through treatment - the eGFR 30 boundary is the only one that changes the dose, so it has to be tracked rather than assumed stable
  • Serum free light chains and calcium as part of myeloma response assessment: they are what a creatinine rise on this drug most often reflects
  • Complete blood count at least weekly during any interruption for neutropenia or thrombocytopenia, per the label's dose-modification table
  • Signs and symptoms of venous and arterial thromboembolism throughout treatment, including after dose interruptions
  • Platelet count before working up hematuria, since the label folds it into a composite hemorrhage term in a drug that causes grade 4 thrombocytopenia

Key trials & series

  • EXCALIBER-RRMM (NCT04975997; phase 3, two-stage, randomized, open-label) - the registrational study: iberdomide 1 mg with subcutaneous daratumumab/hyaluronidase and dexamethasone versus daratumumab/hyaluronidase, bortezomib and dexamethasone after one or two prior lines, with MRD-negative complete response as the major efficacy outcome. The label's MRD primary analysis group was the first 420 patients randomized (207 versus 213) and its safety population 204 per arm. Primary results are not yet published - PubMed carries only the protocol paper (Lonial, Future Oncol 2025), so every safety figure in this profile is label-sourced.
  • CC-220-MM-001 (Lonial, Lancet Haematol 2022) - multicohort phase 1/2 across 42 centres that escalated oral iberdomide 0.3 to 1.6 mg on Days 1 to 21 with weekly dexamethasone in heavily pretreated relapsed/refractory myeloma, establishing the dose and the safety profile. No renal endpoint.
  • Dedicated renal-impairment study pooled into a parent-metabolite population PK model (Chen, J Pharm Sci 2025) - 26 subjects spanning renal function, including severe impairment and kidney failure on intermittent hemodialysis, given a single oral 1 mg dose with plasma, urine and dialysate sampling, then pooled with 354 patients from four other trials. This is the direct evidence behind the label's renal dosing, including the dialysis exception.
  • Iberdomide, ixazomib and dexamethasone at first relapse in older patients (Touzeau, Br J Haematol 2025) - phase 2 combination context in an elderly population; no renal endpoint reported.

Clinical pearls

  • The renal dose reduction has a hole in the middle of it: below eGFR 30 you drop to 0.75 mg, unless the patient is on intermittent hemodialysis, in which case you do not. Dialysis restores clearance to roughly normal; untreated advanced CKD does not.
  • The comparator arm is the whole argument. Renal impairment 11% against 8%, grade 3-4 3.4% against 3.9% - in a disease where the kidney is a target organ, a single-arm rate would have looked like nephrotoxicity.
  • Do not carry lenalidomide's renal dosing habits across. Lenalidomide is about 80% renally cleared and needs a dose at every CKD stage; iberdomide clears mainly by CYP3A and needs one only below eGFR 30.
  • A CYP3A inhibitor changes the dose more often than the kidney does - strong inhibitors are to be avoided outright, and a moderate one drops the dose to the same 0.75 mg the severe-CKD threshold does.
  • Hematuria sits inside the label's composite hemorrhage term rather than in its renal row, in a drug that causes grade 4 thrombocytopenia - check the platelet count before working red urine up as glomerular.

Anticancer mechanism

Oral cereblon E3 ubiquitin ligase modulator (CELMoD) that binds cereblon with greater affinity than the earlier immunomodulatory drugs and drives ubiquitination and degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), producing both direct myeloma-cell death and immune activation. Given as 1 mg orally once daily on Days 1 to 21 of a 28-day cycle in combination with subcutaneous daratumumab and hyaluronidase-fihj and dexamethasone. The August 2026 approval is an accelerated approval based on minimal residual disease-negative complete response, a surrogate endpoint; continued approval may be contingent on confirmatory trials.

Guidelines & consensus

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

7 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.A population pharmacokinetic analysis to evaluate the impact of renal impairment on the pharmacokinetics of iberdomide.Chen P et al. · J Pharm Sci · 2025 · PMID 39870177
  2. 2.Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial.Lonial S et al. · Lancet Haematol · 2022 · PMID 36209764
  3. 3.EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma.Lonial S et al. · Future Oncol · 2025 · PMID 40346992
  4. 4.Model-based analysis for the population pharmacokinetics of iberdomide and its major active metabolite in healthy subjects and patients with relapsed and refractory multiple myeloma.Cheng Y et al. · Br J Clin Pharmacol · 2023 · PMID 35981078
  5. 5.Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects.Gaudy A et al. · Eur J Clin Pharmacol · 2021 · PMID 32965548
  6. 6.Iberdomide, ixazomib and dexamethasone in elderly patients with multiple myeloma at first relapse.Touzeau C et al. · Br J Haematol · 2025 · PMID 39757748
  7. 7.Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma.Amatangelo M et al. · Cell Rep Med · 2024 · PMID 38776914
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.