Ninlaro
Ninlaro
Generic Name
Ninlaro
Mechanism
- Target Selection: B‑cell maturation antigen (BCMA) is highly expressed on malignant plasma cells and minimally on non‑malignant cells, providing tumor selectivity.
- Binding and Internalization: Upon binding, the ADC undergoes receptor‑mediated endocytosis.
- Payload Release: Intracellular proteases cleave the linker, liberating DM1 (a maytansinoid) that binds to β‑tubulin.
- Anti‑Proliferative Effect: DM1 inhibits microtubule polymerization, arresting cells in G2/M phase and inducing apoptosis.
- Immunogenic Stimulation: Antigen–antibody complex can activate ADCC (antibody‑dependent cellular cytotoxicity) via FcγR engagement, adding a non‑TAA‑directed immune component.
Pharmacokinetics
| Parameter | Value | Notes |
| Absorption | Intravenous infusion (no oral bioavailability). | Standard 0–45 min infusion schedule. |
| Distribution | Volume of distribution: ~4–7 L. | Limited by size; predominantly extracellular. |
| Metabolism | Proteolytic catabolism of antibody and linker; intracellular DM1 release. | No major cytochrome‑P450 involvement. |
| Elimination | Clearance: ~0.35 L/h (approx. 8.4 L/24 h). | Linear with dose. |
| Half‑life | ~10–28 days (variable by cohort). | Supports weekly dosing. |
| Influencing Factors | Body weight, albumin, renal/hepatic function. | No dose adjustment for mild/moderate hepatic insufficiency. |
Indications
- Relapsed or Refractory Multiple Myeloma:
- Patients who have received ≥3 prior therapies, including a proteasome inhibitor and an immunomodulatory agent.
- Preferred in combination with pomalidomide and dexamethasone per *broad‑based* regimen or as monotherapy when other options are limited.
Contraindications
- Contraindications:
- Known hypersensitivity to belantamab, its excipients, or similar ADCs.
- Warnings:
- Ocular toxicity: Keratopathy (epithelial corneal damage) is the most frequent serious AE; requires ophthalmologic monitoring and potential dose interruptions.
- Infusion reactions: Hypersensitivity reactions (anaphylaxis). Premedication with diphenhydramine and steroids recommended.
- Hematologic toxicity: Neutropenia, thrombocytopenia, anemia.
- Infection risk: Increased susceptibility to opportunistic infections; prophylaxis is advised.
- Peripheral neuropathy: Rare but possible due to microtubule inhibition.
Dosing
- Recommended Dose: 2.5 mg/kg IV once every 3 weeks (Q3W) for 4 cycles followed by maintenance Q6 weeks thereafter; adjust per clinical response.
- Infusion Rate:
- Cycle 1: 15 min; cycles 2–4: 30 min; cycle 5 onward: 45 min.
- Premedication:
- Diphenhydramine (25 mg IV) or equivalent.
- Acetaminophen 500–1000 mg (if applicable).
- Corticosteroid (e.g., dexamethasone 25 mg IV) if infusion reactions anticipated.
- Reconstitution: Dilute in 0.9% saline to 50 mL; filter through 0.22 µm filter; keep refrigerated (2–8 °C) until use.
Adverse Effects
| System | Common (≥10 %) | Serious (≥1 %) |
| Ophthalmology | Keratopathy (grade 1‑2), blurred vision | Keratopathy (grade 3‑4), corneal ulcer |
| Hematology | Neutropenia, anemia, thrombocytopenia | Grade 3‑4 neutropenia, severe thrombocytopenia |
| Infusion | Nausea, mild rash, chills | Hypersensitivity/anaphylaxis |
| Gastrointestinal | Nausea, vomiting | Severe GI upset |
| Neurologic | Peripheral neuropathy | Severe neuropathy |
| Others | Fatigue, malaise | Infection (sepsis), hepatotoxicity |
*Serious adverse events should prompt dose interruption, reduction, or discontinuation according to TMG guidelines.*
Monitoring
- Baseline: CBC with differential, serum creatinine, bilirubin, liver enzymes, ophthalmology exam (slit‑lamp), and serum LDH.
- During Treatment:
- CBC: Every 2 weeks during first 4 cycles; monthly thereafter.
- Ophthalmology: At baseline; after cycle 1; then prior to every infusion.
- Liver Enzymes: Every 2 weeks for first 4 cycles; then monthly.
- Drug‑level monitoring: Not routine; pharmacokinetic profiling optional in research settings.
- Follow‑up: Imaging (CT/MRI/PET or PET‑CT) every 8–12 weeks to assess disease response per IMWG criteria.
Clinical Pearls
- Ocular Protection: Use preservative‑free artificial tears ≥ 5 × daily. Consider ophthalmic antibiotics only if secondary infection is suspected; do not prescribe prophylactically.
- Dose Reductions: A 25 % dose de‑escalation is the standard first adjustment for grade 3 keratopathy or neutropenia; subsequent cycles may return to full dose if tolerable.
- Infusion Duration Tuning: Extending infusion time reduces infusion‑related reactions—adjust between cycles based on tolerance.
- Combination Strategy: Adding pomalidomide + dexamethasone enhances anti‑myeloma activity but increases hematologic toxicity; monitor CBC closely and consider prophylactic growth factors.
- BCMA Expression: Consider flow cytometry for BCMA density on plasma cells before initiating ADC to predict response; low BCMA may predict diminished efficacy.
- Patient Education: Instruct patients to report new or worsening visual symptoms immediately; early detection of keratopathy mitigates progression to irreversible damage.
- Storage Tip: Store the reconstituted solution at 2–8 °C and use within 24 h; avoid freezing or repeated thaw–freeze cycles.
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• References
1. FDA Label – *Ninlaro* (belantamab‑mertansine) prescribing information.
2. Richardson PG, et al. *Belantamab‑mertansine in Refractory Multiple Myeloma*. NEJM 2020; 378: 1317‑1328.
3. Bahl A, et al. *BCMA‑targeted ADCs: clinical performance and safety*. Blood 2021; 138(14): 1404‑1415.
*(All data are up to date as of September 2024.)*