Velcade | Pharmacology Mentor

Generic Name

Velcade®

Mechanism

Proteasome inhibition: Binds irreversibly to the chymotrypsin‑like (β5) subunit, blocking proteolysis of intracellular proteins.
Accumulation of misfolded proteins → induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR).
Apoptosis: Triggered by oxidative stress, DNA damage, and inhibition of NF‑κB signaling.
Synergy: Modulates tumor microenvironment, enhances anti‑neoplastic effects of alkylating agents and immunomodulatory drugs.

Pharmacokinetics

Parameter	Value	Notes
Absorption	Poor oral bioavailability (~10 %); only parenteral routes used	IV and SC are standard
Distribution	Extensive; volume of distribution ≈ 26 L; protein binding ~ 40 %	Accumulates in liver, spleen, bone marrow
Metabolism	Hepatic CYP3A4/3A5 mediated	Major pathway; minor UGT-mediated conjugation
Elimination	Renal (≈ 30 %) and fecal	Half‑life ~ 9–11 h (IV), ~ 9 h (SC)
Drug–drug interactions	Potentiated by CYP3A4 inhibitors (ketoconazole, clarithromycin) → ↑ serum levels; reduced by strong inducers (rifampin, carbamazepine)	Monitor for toxicity

Indications

Relapsed or refractory multiple myeloma in patients ≥ 18 yrs.
New‑ly diagnosed multiple myeloma (combination regimens: VAD, VRd, Velcade‑lenalidomide‑dex, etc.).
Smoldering myeloma (clinical trials; not routine).
Transplant‑eligible patients post‑autologous stem‑cell transplant as maintenance (clinical data emerging).

Contraindications

Known hypersensitivity to bortezomib or any component.
Severe hepatic impairment (Child‑Pugh C) – avoid.
Pregnancy: Category D; teratogenic risk; contraindicated.
Peripheral neuropathy > Grade 2 (per CTCAE) – dose reduction or discontinuation.
Infections: Elevated risk for opportunistic infections; prophylaxis may be required.
Cardiac: QTc prolongation uncommon; still monitor in patients on QT‑prolonging drugs.

Dosing

Regimen	Dose	Schedule	Administration
IV	1.3 mg/m²	Days 1, 4, 8, 11 of a 28‑day cycle	1‑hour infusion
SC	1.3 mg/m²	Days 1, 4, 8, 11 (or 5‑2‑5 for 15‑day cycle)	Subcutaneous

• Renal/hepatic adjustments: No formal dose adjustment, but monitor closely.
• Rescue dose: 1.5 mg/m² if 1.3 mg/m² inadequate after 2 cycles.
• Combination dosing: Coordinate with other agents (e.g., dexamethasone 40 mg qod) to minimize toxicity.

Adverse Effects

Adverse Effect	Frequency	Management
Peripheral neuropathy	Up to 25 % (grade 2‑3)	Dose reduction, switch to SC, duloxetine/acetyl‑cysteine adjunct, neuro‑protective agents
Anemia, thrombocytopenia, neutropenia	10–20 %	Growth factors (G‑CSF, EPO), transfusions
Gastrointestinal: nausea, vomiting, diarrhea	< 15 %	Antiemetics, anti‑diarrheals
Fatigue, anorexia	10–20 %	Counseling, nutritional support
Infections: febrile neutropenia, viral reactivation	< 5 %	Prophylactic antivirals (valaciclovir) for HHV‑6
Cardiotoxicity: arrhythmias, left ventricular ejection fraction drop	Rare	ECG, echocardiogram baseline/periodic
Hand‑foot syndrome	< 5 %	Dose hold, topical emollients

Monitoring

Baseline labs: CBC with diff., CMP, LDH, β‑2 microglobulin, serum/urine protein electrophoresis.
Peripheral neuropathy: Neurologic exam every cycle; patient diary of numbness/tingling.
Renal/hepatic function: Every cycle; adjust supportive therapy.
Infection surveillance: Monitor for fever; HLA‑B27‑positive patients may need specific prophylaxis.
Cardiovascular: Baseline ECG, LVEF; repeat if arrhythmias.
Serum drug levels: Not routinely measured but may be considered in refractory cases.

Clinical Pearls

SC > IV: Subcutaneous administration reduces peripheral neuropathy and improves patient convenience without compromising efficacy.
“Rescue” dosing: After 2 cycles of ineffective control, increase to 1.5 mg/m² may salvage response; use only if neuropathy < grade 1.
Combination strategy: Pair with immunomodulatory drugs (lenalidomide, thalidomide) or alkylating agents for synergistic cytotoxicity.
Neuro‑protection: Early initiation of duloxetine 30 mg daily at low dose can mitigate neuropathic pain.
Drug‑drug caution: CYP3A4 inhibitors (ketoconazole, erythromycin) can increase bortezomib exposure; adjust other potent inhibitors rather than dose.
Prophylactic antivirals: Consider valacyclovir 500 mg BID for patients with prior HHV‑6 encephalitis; check baseline serology.
Early tapering: In patients who develop high‑grade neuropathy, a dose‑reduction strategy (⅔ or ⅕ of scheduled dose) maintains disease control while preserving quality of life.
Patient education: Discuss the importance of promptly reporting tingling, numbness, or weakness to reduce severe neuropathy.

Velcade remains a critical therapeutic agent for multiple myeloma, with a robust evidence base supporting its use both as monotherapy and in combination regimens. Proper dosing, vigilant monitoring, and proactive management of adverse effects are essential for optimizing patient outcomes.