Proteasome Inhibitor

Aka: Proteasome Inhibitor, Proteosome Inhibitor, Bortezomib, Velcade, Carfilzomib, Kyprolis, Ixazomib, Ninlaro

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II. Indications

  1. Bortezomib (Velcade)
    1. Multiple Myeloma (FDA approved)
    2. Mantle Cell Lymphoma (FDA approved)
    3. Waldenstrom's Macroglobulinemia
    4. Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma
    5. Systemic Light Chain Amyloidosis
  2. Carfilzomib (Kyprolis)
    1. Multiple Myeloma (refractory, FDA approved)
  3. Ixazomib (Ninlaro)
    1. Multiple Myeloma (FDA approved)

III. Mechanism

  1. Proteasomes are enzyme complexes that degrade (proteolyse) ubiquitinated Proteins
    1. Ubiquitinated Proteins have been tagged with ubiquitin, marked for disposal
  2. Proteasome Inhibitors block the normal disposal of Proteins and cell homeostasis
    1. Results in accumulation of intracellular poly-ubiquitinated Proteins
    2. Results in cell cycle arrest, apoptosis and the inhibition of neoplasm growth

IV. Medications

  1. Intravenous Proteasome Inhibitors
    1. Bortezomib (Velcade)
      1. Dipeptide boronic acid analog inhibits 26S proteasome, nuclear factor (NF)-kappaB
    2. Carfilzomib (Kyprolis)
      1. Epoxomicin derivative, irreversibly binds to and inhibits 20S catalytic core subunit (chymotrypsin-like activity)
  2. Oral Proteasome Inhibitors
    1. Ixazomib (Ninlaro)
      1. Boron-based Proteasome Inhibitor binds to and inhibits the 20S catalytic core subunit

V. Adverse Effects: Bortezomib (Velcade)

  1. Acute Respiratory Distress Syndrome
  2. Gastrointestinal (Nausea, Vomiting, Diarrhea)
  3. Heart Failure
  4. Peripheral Neuropathy
  5. Pneumonia
  6. Orthostatic Hypotension
  7. Myelosuppression
    1. Neutropenia
    2. Thrombocytopenia
  8. Other rare effects
    1. Acute Liver Failure
    2. Stephen Johnson Syndrome
    3. Thrombotic Microangiopathy (TTP, HUS)
    4. Blepharitis

VI. Adverse Effects: Carfilzomib (Kyprolis)

  1. Heart Failure
  2. Coronary Ischemia
  3. Pulmonary Hypertension
  4. Infusion reaction (pretreat with Dexamethasone)
  5. Other rare effects
    1. Posterior Reversible Encephalopathy Syndrome (PRES)
    2. Thrombotic Microangiopathy (TTP, HUS)

VII. Adverse Effects: Ixazomib (Ninlaro)

  1. Edema
  2. Gastrointestinal (Nausea, Vomiting, Diarrhea)
  3. Hepatotoxicity
  4. Myelosuppression (avoid if ANC <1k or Platelet Count <75k)
    1. Neutropenia
    2. Thrombocytopenia
  5. Peripheral Neuropathy
  6. Herpes Zoster
    1. Consider VZV prophylaxis

VIII. Safety

  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters)
    1. Use reliable Contraception
  3. Monitoring
    1. Complete Blood Count
    2. Liver Function Tests (Ixazomib)

IX. Drug Interactions

  1. CYP3A Inducers
    1. Avoid with Ixazomib (Ninlaro)

X. Resources

  1. Bortezomib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1521d321-e724-4ffc-adad-34bf4f44fac7
  2. Carfilzomib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea66eb30-e665-4693-99a1-a9d3b4bbe2d6
  3. Ixazomib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=038f2461-834b-4488-9ebd-863c83eef5a7

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