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. Dosing

  1. See other references for disease specific dosing protocols

VI. Adverse Effects: Bortezomib (Velcade)

VII. 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)

VIII. 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

IX. 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)

X. Drug Interactions

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

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Related Studies

Ontology: bortezomib (C1176309)

Definition (NCI_NCI-GLOSS) A drug used to treat multiple myeloma. It is also used to treat mantle cell lymphoma in patients who have already received at least one other type of treatment and is being studied in the treatment of other types of cancer. Bortezomib blocks several molecular pathways in a cell and may cause cancer cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid.
Definition (NCI) A dipeptide boronic acid analogue with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy.
Definition (PDQ) A dipeptide boronic acid analogue with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=43560&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=43560&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1851" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C400082
SnomedCT 398907002, 407097007
English [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, bortezomib (medication), bortezomib [Chemical/Ingredient], bortezomib, Bortezomib (product), Bortezomib, Bortezomib (substance), BORTEZOMIB
Spanish bortezomib (producto), bortezomib, bortezomib (sustancia)

Ontology: Proteasome inhibitor (C1443643)

Definition (MSH) Compounds that inhibit the function or proteolytic action of the PROTEASOME.
Definition (NCI_NCI-GLOSS) A drug that blocks the action of proteasomes. A proteasome is a large protein complex that helps destroy other cellular proteins when they are no longer needed. Proteasome inhibitors are being studied in the treatment of cancer.
Definition (NCI) Any substance that inhibits the proteasome complex, an enzyme complex responsible for degradation of ubiquitinated proteins. Inhibition of proteasome activity and ubiquitin-proteasome mediated proteolysis results in an accumulation of poly-ubiquitinated proteins, which may result in the disruption of cellular processes, cell cycle arrest, the induction of apoptosis, and the inhibition of tumor growth and angiogenesis.
Concepts Pharmacologic Substance (T121)
MSH D061988
SnomedCT 409217006, 409218001
English Proteasome inhibitor, Proteasome Inhibitors, Proteasome Endopeptidase Complex Inhibitors, Proteasome Inhibitor, Inhibitors, Proteasome, Inhibitor, Proteasome, proteasome inhibitor, Proteasome inhibitor (product), Proteasome inhibitor (substance)
Czech inhibitory proteasomu, inhibitory proteazomu
French Inhibiteurs du complexe endopeptidasique du protéasome, Inhibiteurs du protéasome, Inhibiteurs du complexe multienzymatique du protéasome, Inhibiteurs du complexe d'endopeptidases du protéasome
German Proteasomeninhibitoren, Proteasomeninhibitor, Proteasome Endopeptidase Complex Inhibitors
Italian Inibitori del proteasoma
Spanish Inhibidores de Proteasoma, Inhibidores Proteasomales, inhibidor de proteasoma (producto), inhibidor de proteasoma (sustancia), inhibidor de proteasoma
Polish Inhibitory proteasomu
Russian ПРОТЕАСОМ ЭНДОПЕПТИДАЗНОГО КОМПЛЕКСА ИНГИБИТОРЫ, PROTEASOM INGIBITORY, ПРОТЕАСОМ ИНГИБИТОРЫ, PROTEASOM ENDOPEPTIDAZNOGO KOMPLEKSA INGIBITORY
Portuguese Inibidores de Proteassoma

Ontology: carfilzomib (C2001856)

Definition (NCI) An epoxomicin derivate with potential antineoplastic activity. Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S catalytic core subunit of the proteasome, a protease complex responsible for degrading a large variety of cellular proteins. Inhibition of proteasome-mediated proteolysis results in an accumulation of polyubiquinated proteins, which may lead to cell cycle arrest, induction of apoptosis, and inhibition of tumor growth.
Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
MSH C524865
English carfilzomib, Carfilzomib, (2S)-N-((1S)-1-Benzyl-2-(((1S)-3-methyl-1-(((2R)-2-methyloxiran-2-yl)carbonyl)butyl)amino)-2-oxoethyl)-4-methyl-2-(((2S)-2-((morpholin-4-ylacetyl)amino)-4-phenylbutanoyl)amino)pentanamide, CARFILZOMIB, chemotherapeutics carfilzomib, carfilzomib (medication)