Proteasome inhibitors

Definition and Overview

Proteasome inhibitors are a class of anticancer agents that selectively target the 26S proteasome, a protein complex responsible for degrading ubiquitin-tagged intracellular proteins. By inhibiting proteasome activity, these drugs disrupt protein homeostasis, leading to accumulation of damaged or misfolded proteins, triggering apoptosis, especially in highly proliferative malignant cells such as multiple myeloma and mantle cell lymphoma.

The clinical impact of proteasome inhibition has been most prominent in the treatment of hematological malignancies, where dysregulated protein turnover is central to pathogenesis. These inhibitors represent a hallmark of targeted cancer therapy and have paved the way for novel combination regimens.

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1. Mechanism of Action

Proteasome inhibitors block the activity of the chymotrypsin-like site of the 20S core particle of the 26S proteasome. This prevents the breakdown of intracellular proteins involved in:

• Cell cycle progression

• Apoptosis regulation

• Immune response

• DNA repair

• Stress response

By disrupting these processes, proteasome inhibitors promote:

• Cell cycle arrest at G2/M

• Activation of pro-apoptotic pathways (e.g., upregulation of p53, Bax)

• Inhibition of NF-κB signaling, which is dependent on proteasomal degradation of IκB

• Accumulation of polyubiquitinated proteins, leading to ER stress and unfolded protein response (UPR)

This mechanism is particularly effective against plasma cells in multiple myeloma, which are highly dependent on proteasome function due to their high protein production.

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2. Approved Proteasome Inhibitors

A. First-Generation Inhibitors

1. Bortezomib

   • Brand name: Velcade

   • Reversible inhibitor of the 26S proteasome

   • FDA-approved for:

     • Multiple myeloma (MM)

     • Mantle cell lymphoma (MCL)

B. Second-Generation Inhibitors

2. Carfilzomib

   • Brand name: Kyprolis

   • Irreversible selective inhibitor of the chymotrypsin-like activity of the proteasome

   • Approved for:

     • Relapsed/refractory MM in combination with lenalidomide and dexamethasone

3. Ixazomib

   • Brand name: Ninlaro

   • Oral, reversible proteasome inhibitor

   • Approved for:

     • Relapsed/refractory MM in combination with lenalidomide and dexamethasone

C. Emerging/Investigational Inhibitors

4. Oprozomib – Oral analog of carfilzomib, in clinical trials

5. Marizomib – Irreversible pan-proteasome inhibitor with CNS penetration, evaluated for glioblastoma

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3. Therapeutic Indications

Indication	Agents Used
Multiple Myeloma	Bortezomib, Carfilzomib, Ixazomib
Mantle Cell Lymphoma	Bortezomib
Waldenström's Macroglobulinemia	Investigational use
AL Amyloidosis	Off-label use
Relapsed Non-Hodgkin Lymphoma	Clinical trials
Solid Tumors (e.g., lung, breast, pancreas, GBM)	Limited/experimental

4. Pharmacokinetics and Pharmacodynamics

Drug	Administration	Half-life	Metabolism	Notes
Bortezomib	IV or subcutaneous	~9–15 h	Hepatic (CYP3A4)	SubQ preferred to reduce neuropathy
Carfilzomib	IV	~1 h	Peptidase metabolism	Irreversible; shorter plasma half-life but longer proteasome inhibition
Ixazomib	Oral	~9.5 days	CYP3A4, CYP1A2	Requires enteric absorption; dosed weekly

5. Dosing Guidelines

Bortezomib

• Dose: 1.3 mg/m² twice weekly for 2 weeks (days 1, 4, 8, 11) of a 21-day cycle

• Route: Subcutaneous preferred

• Combination: Often used with cyclophosphamide, thalidomide/lenalidomide, dexamethasone

Carfilzomib

• Dose: 20 mg/m² on days 1 and 2 of cycle 1, escalated to 27 mg/m²

• Route: IV over 10–30 minutes

• Cycles: 28-day cycles; multiple regimens (twice-weekly or once-weekly)

Ixazomib

• Dose: 4 mg orally on days 1, 8, 15 of a 28-day cycle

• Used with: Lenalidomide and dexamethasone

• Oral: Only oral proteasome inhibitor currently approved

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6. Adverse Effects

Common Side Effects

• Gastrointestinal: Diarrhea, constipation, nausea

• Fatigue and anorexia

• Hematological: Thrombocytopenia, anemia, neutropenia

Severe Toxicities

• Peripheral neuropathy: Especially with bortezomib; reduced with subcutaneous route

• Cardiotoxicity: Particularly with carfilzomib; includes CHF, hypertension

• Pulmonary toxicity: Dyspnea, rare pulmonary edema

• Hepatotoxicity

• Infections: Reactivation of herpes zoster (use prophylaxis)

• Tumor lysis syndrome

• Thrombotic microangiopathy (rare)

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7. Contraindications and Precautions

Contraindication	Clinical Notes
Hypersensitivity	Includes reactions to boron or mannitol (in bortezomib)
Severe hepatic impairment	May require dose reduction or avoidance
Severe cardiac conditions	Caution with carfilzomib
Peripheral neuropathy	Dose adjustment or discontinuation
Pregnancy and lactation	Category D – teratogenic

8. Drug Interactions

Drug/Class	Interaction Mechanism	Clinical Implication
Strong CYP3A4 inhibitors (e.g., ketoconazole)	↑ plasma levels of bortezomib/ixazomib	Increased toxicity
CYP3A4 inducers (e.g., rifampin, phenytoin)	↓ efficacy by reducing drug levels	Avoid co-administration
Antivirals (e.g., acyclovir)	Used prophylactically	Prevent herpes zoster reactivation
Warfarin	Altered INR	Monitor coagulation status closely
Digoxin	Narrow therapeutic index	Monitor serum digoxin when co-administered

9. Monitoring Parameters

• CBC with differential: Myelosuppression

• Liver function tests

• Renal function (BUN, creatinine)

• Neurologic exams: Peripheral neuropathy monitoring

• Ejection fraction: With carfilzomib in patients with cardiac history

• Signs of infection

• HSV/VZV reactivation

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10. Resistance Mechanisms

Cancer cells may develop resistance to proteasome inhibitors through:

• Upregulation of alternative proteolytic pathways (e.g., lysosomal degradation)

• Mutations in the proteasome subunits

• Activation of drug efflux transporters

• Increased expression of anti-apoptotic proteins

Combination regimens with immunomodulatory drugs (IMiDs) or monoclonal antibodies (e.g., daratumumab) can help overcome resistance.

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11. Clinical Pearls

• Bortezomib SubQ vs. IV: Subcutaneous administration reduces incidence and severity of peripheral neuropathy without compromising efficacy.

• Carfilzomib has less neuropathy than bortezomib but higher cardiovascular risk.

• Ixazomib allows for oral, home-based therapy, improving patient convenience and compliance.

• Use HSV prophylaxis (e.g., acyclovir 400 mg BID) with all proteasome inhibitors to prevent zoster reactivation.

• Proteasome inhibitors are generally used as part of combination regimens and not as monotherapy.

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12. Combination Regimens in Practice

Regimen Name	Components	Indication
VRD	Bortezomib + Lenalidomide + Dexamethasone	First-line MM therapy
KRd	Carfilzomib + Lenalidomide + Dexamethasone	Relapsed/refractory MM
IRd	Ixazomib + Lenalidomide + Dexamethasone	Oral option for relapsed MM
VMP	Bortezomib + Melphalan + Prednisone	Elderly MM patients
VD	Bortezomib + Dexamethasone	Maintenance or frail patients

13. Future Developments

• Marizomib: Being studied in glioblastoma, crosses the blood–brain barrier

• Oprozomib: Oral analog of carfilzomib, under investigation

• Combination with immunotherapies: Synergistic effects with CAR-T, bispecific antibodies

• Biomarker development: For prediction of response and resistance