Cyclophosphamide
Cytoxan · Oxazaphosphorine alkylator
Vasopressin-independent hyponatremia; hemorrhagic cystitis.
SIADHCYST
MildOpen →
XPO1 (nuclear export) inhibitor
Selinexor
Xpovio · SELI
A first-in-class nuclear-export inhibitor whose dose-limiting toxicity is hyponatremia — usually grade >=3 and front-loaded.
ModerateXPO1 (nuclear export) inhibitor · approved 2019
Multiple myeloma (with bortezomib/dexamethasone after >=1 prior therapy; with dexamethasone in penta-refractory disease)Relapsed or refractory diffuse large B-cell lymphoma after >=2 lines
Signature kidney injury
SIADH / Hyponatremia
Representative incidence22%
Hyponatremia is common and dose-limiting. In STORM it occurred in ~22% of patients and was predominantly grade >=3 — the most common grade >=3 non-hematologic toxicity. In BOSTON any-grade hyponatremia affected roughly a third of the selinexor arm (grade 3-4 ~8-9%); in SADAL grade 3-4 hyponatremia occurred in ~8%.
Source: Chari et al., NEJM 2019
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / Endothelium
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
SIADH / Hyponatremia
Inappropriate water retention at the collecting duct — high-dose cyclophosphamide.
Mechanism of kidney injury
Hyponatremia is the signature electrolyte toxicity — an SIADH-like physiology often compounded by gastrointestinal sodium and volume losses from nausea, vomiting, diarrhea and anorexia. Selinexor is not a direct tubular nephrotoxin; associated AKI is typically prerenal from volume depletion. In myeloma, exclude pseudohyponatremia from a high paraprotein.
Clinical presentation
A falling serum sodium (often asymptomatic; grade 3-4 is Na <125 mmol/L) with prominent nausea, vomiting, diarrhea, anorexia, weight loss and fatigue; cytopenias are also common. The disturbance clusters in cycles 1-2.
Onset
Early — within the first cycle/few weeks; front-loaded.
Reversibility
Reversible
Anticancer mechanism
First-in-class oral selective inhibitor of nuclear export (SINE) that covalently binds exportin-1 (XPO1/CRM1), blocking nuclear export of tumor-suppressor proteins (p53, IkB, FOXO, p21) and of oncoprotein mRNAs (c-myc, cyclin D, Bcl-2). The resulting nuclear retention reactivates tumor suppressors and triggers cell-cycle arrest and apoptosis.
Management
Correct sodium per standard protocols (limit correction to ~8-10 mmol/L per 24 h to avoid osmotic demyelination), hydrate, and escalate antiemetics. Interrupt and dose-reduce for grade 3-4 hyponatremia, treating to Na >=130 mmol/L before resuming.
Risk factors
- Baseline hyponatremia or poor oral intake
- Advanced age/frailty and poor performance status
- Concurrent diuretics or other SIADH-inducing drugs
- Inadequate antiemetic prophylaxis and dehydration
Prevention
- Mandatory prophylactic antiemetics (5-HT3 antagonist with or without olanzapine and an NK1 antagonist)
- Hydration and nutritional support
- Baseline and serial sodium monitoring (at least weekly early)
Note · Recent (2019) agent with strong, quantified electrolyte data; flagged for the onconephrology audience because hyponatremia is common and dose-limiting.
Clinical depth
Renal dose adjustment
Limited renal data; no dedicated adjustment for mild-moderate renal impairment is established, and severe CKD/dialysis are not well studied — individualize with onconephrology input. Dose is otherwise modified for hyponatremia and cytopenias.
Dialyzability & ESKD dosing
Not established; highly protein-bound and not expected to be meaningfully dialyzable.
Differential diagnosis
Distinguish SINE/SIADH-like hyponatremia from hypovolemic hyponatremia (GI losses), pseudohyponatremia (myeloma paraprotein) and diuretic-induced hyponatremia; and prerenal AKI from myeloma cast nephropathy, hypercalcemia or contrast.
Monitoring
- Serum sodium and a full metabolic panel at baseline and each cycle (more often early or with symptoms)
- CBC weekly initially (thrombocytopenia, neutropenia)
- Weight, fluid status and nutrition
- Symptom/antiemetic-response review
Key trials & series
- STORM (Chari, NEJM 2019) — pivotal trial; hyponatremia ~22%, predominantly grade >=3
- BOSTON (Grosicki, Lancet 2020) — phase 3 in myeloma after >=1 prior line
- SADAL (Kalakonda, Lancet Haematol 2020) — pivotal DLBCL trial
Clinical pearls
- STORM hyponatremia was overwhelmingly grade >=3 — check sodium at least weekly early; it is dose-limiting, not a nuisance.
- Scheduled multi-agent antiemetic prophylaxis plus hydration is the highest-yield intervention because much of the hyponatremia/AKI is GI-loss-driven.
- In myeloma, exclude pseudohyponatremia from paraprotein and correct sodium slowly.
- Toxicity is front-loaded (cycles 1-2) and managed with dose interruption/reduction.
Where it strikes
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
SIADH / HyponatremiaElectrolyte WastingPrerenal / Hemodynamic AKI
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkOral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.Chari A et al. · N Engl J Med 2019 · PMID 31433920Pivotal STORM trial supporting accelerated approval and the key hyponatremia data.PMIDOnce-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial.Grosicki S et al. · Lancet 2020 · PMID 33189178Phase 3 establishing the selinexor/bortezomib/dexamethasone regimen with its hyponatremia signal.PMIDSelinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.Kalakonda N et al. · Lancet Haematol 2020 · PMID 32589977Pivotal DLBCL trial reporting grade 3-4 hyponatremia.PMIDSelinexor, selective inhibitor of nuclear export: Unselective bullet for blood cancers.Benkova K et al. · Blood Rev 2020 · PMID 32972802Comprehensive XPO1/CRM1 SINE mechanism review.PMIDNuclear Export Inhibition for Pancreatic Cancer Therapy.Muqbil I et al. · Cancers (Basel) 2018 · PMID 29735942Mechanistic review of XPO1 overexpression and SINE-mediated tumor-suppressor restoration.PMIDCancer therapy in patients with reduced kidney function.Karam S et al. · Nephrol Dial Transplant 2024 · PMID 38914465Onconephrology review of anticancer renal toxicity and electrolyte disturbances including hyponatremia.PMIDToxicity management strategies for next-generation novel therapeutics in multiple myeloma.Steinbach M et al. · Ther Adv Hematol 2022 · PMID 35860442Practical management of selinexor GI toxicity, hyponatremia and dose modification.