Bortezomib

Bortezomib is the first approved proteasome inhibitor used as monotherapy or combination therapy. Bortezomib reversibly and highly selectively inhibits the chymotrypsin-like activity of 26S proteasomes. Proteasomes are intracellular multiprotease complexes involved in the degradation of numerous proteins. This mechanism is essential for cell cycle and survival.

Inhibition of the NFκB signaling pathway. Downregulation of various NFκB-mediated mechanisms, such as cell proliferation, invasion, metastasis, and angiogenesis, occurs.

Programmed cell death signaling pathways.

Furthermore, proteasome inhibition leads to activation of c-Jun NH2-terminal kinase (JNK), which leads to programmed cell death via various caspases.

Proteasome inhibitonm also activates the tumor suppressor protein p53. This leads to apoptosis via the proapoptotic NOXA as well as caspases. NOXA can also be induced independently of p53. Other proapoptotic proteins, normally regulated by proteasomes, also accumulate and induce cell death.

Inhibition of multiprotease complexes leads to increased accumulation of defective proteins in the cell. Proteins are generally assembled in the endoplasmic reticulum (ER), where they also undergo quality control. Misfolded proteins are fed to the proteasomes. An excessive amount of protein leads to insufficiency symptoms of the endoplasmic reticulum. These are further exacerbated by the accumulation of misfolded proteins during proteasome inhibition. A "UPR/unfolded protein response" occurs, which reduces protein synthesis and, in the case of severe ER stress, can also trigger apoptosis at the same time.

Bortezomib is administered intravenously or subcutaneously as a peptide. Following intravenous bolus administration or subcutaneous injection in patients with multiple myeloma, equivalent total systemic exposure was observed after repeated dose administration. The maximum plasma concentration was lower with subcutaneous administration than with intravenous administration.

Inhibition of multiprotease complexes results in increased accumulation of defective proteins in the cell. Proteins are generally assembled in the endoplasmic reticulum (ER) and subjected to quality control, and misfolded proteins are delivered to proteasomes. An excessive amount of protein leads to insufficiency symptoms of the endoplasmic reticulum. These are further exacerbated by the accumulation of misfolded proteins during proteasome inhibition. A "UPR/unfolded protein response" occurs, which reduces protein synthesis and, in the case of severe ER stress, can also trigger apoptosis at the same time.

Treatment should be given only under the supervision of a physician experienced in cancer therapy. Bortezomib is commercially available in the form of a mannitol-boronic acid ester as a powder for the preparation of a solution for injection or as a ready-to-use solution for injection. Once prepared, it is administered as a subcutaneous or intravenous injection, depending on the concentration of the solution.

Progressive multiple myeloma as monotherapy or in combination with doxorubicin or dexamethasone in adults who have undergone at least one prior therapy and have already undergone or are ineligible for hematopoietic stem cell transplantation

Previously untreated multiple myeloma in combination with melphalan and prednisone in adults unsuitable for high-dose chemotherapy with hematopoietic stem cell transplantation

Induction treatment for previously untreated multiple myeloma in combination with dexamethasone or dexamethasone and thalidomide in adults unsuitable for high-dose chemotherapy with hematopoietic stem cell transplantation

Previously untreated mantle cell lymphoma in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone in adults unsuitable for hematopoietic stem cell transplantation

The finished intravenous solution for injection contains 1 mg/ml of bortezomib, and the subcutaneous solution for injection contains 2.5 mg/ml of the active ingredient after preparation.

Bortezomib is used in three- to six-week treatment cycles, depending on the indication and combination partners. A dose of 1.3 mg/m2 of body surface area is recommended. The drug is usually administered once or twice weekly for two weeks, with at least 72 hours between bortezomib doses. A treatment break occurs during the so-called rest phase of the third or sixth week. The number of treatment cycles depends on the indication and patient response

Side effects most common with bortezomib treatment include:

Nausea, vomiting

diarrhea, constipation

fatigue, fever

Thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy)

Headache

Paresthesia

Decreased appetite

Dyspnea

Skin rash

Herpes zoster

Myalgia

Occasionally (≥ 1/1,000 to < 1/100), the following serious adverse reactions may occur during therapy with bortezomib.

Heart failure

Tumor lysis syndrome

Pulmonary hypertension

Posterior reversible encephalopathy syndrome

Acute diffuse infiltrative pulmonary disease

Rarely (≥ 1/10,000 to < 1/1,000) autonomic neuropathy.

The following additional adverse reactions occurred during combination therapy of mantle cell lymphoma with bortezomib and other agents.

Hepatitis B infection (< 1%)

Myocardial ischemia (1.3%)

Increased incidence of hematologic adverse events, peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair growth disorders

Bortezomib itself is a weak inhibitor of the cytochrome P40 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and is metabolized via CYP3A4, CYP2C19 as well as CYP1A2. Therefore, the following interactions should be noted.

• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): increased active levels of bortezomib possible, therefore close monitoring recommended.
• CYP3A4 inducers (e.g., rifampicin, St. John's wort, phenytoin): decreased efficacy possible, use is not recommended
• Diabetic patients taking oral antidiabetic agents are at increased risk for hypo- and hyperglycemia during therapy with bortezomib. Therefore, blood glucose levels should be monitored closely in these patients and antidiabetic drug dosages should be adjusted if necessary.

Hypersensitivity to the active substance

Acute diffuse infiltrative pulmonary and pericardial disease.

Additional contraindications of the active ingredients in combination therapy

Pregnancy

The teratogenic potential of bortezomib has not been conclusively studied; therefore, clinical data on the use of the agent in pregnancy are not yet available. In animal studies, bortezomib showed no effect on embryonic development.

The agent should not be used in pregnancy unless treatment is required based on the woman's clinical condition.

Particular attention should be paid to the contraindication in pregnancy of thalidomide in combination treatment.

Patients who experience constipation should be monitored carefully, as ileus may occasionally occur.

Blood Count: Differential blood counts should be monitored closely throughout treatment with bortezomib. If clinically appropriate, platelet transfusion should be considered.

Gastrointestinal and intracerebral bleeding have been reported in association with bortezomib treatment. Therefore, platelet counts should be checked before each administration of the agent. If the platelet count is <25,000/μl or, in the case of the combination with melphalan and prednisone, ≤30,000/μl, therapy should be suspended. Treatment benefits should be carefully weighed against risks, especially in cases of moderate to severe thrombocytopenia and bleeding risks.

Transient neutropenia has been observed in patients with mantle cell lymphoma, which was reversible between treatment cycles and showed no evidence of cumulative neutropenia. Because patients with neutropenia are at increased risk of infection, they should be monitored for signs and symptoms of infection and treated promptly if necessary. In cases of hematologic toxicity, granulocyte colony-stimulating factors may be used according to local standards. In case of repeated delays in the application of cycles, prophylactic application of granulocyte colony stimulating factors should be considered.

Neuropathy Symptoms: In patients receiving bortezomib in combination with drugs known to be associated with neuropathies (e.g., thalidomide), early and regular monitoring of symptoms of treatment-related neuropathy (sensation of burning, hyperesthesia, hypoesthesia, paresthesia, malaise, neuropathic pain, or weakness) with neurologic examination should be considered. Patients with new onset or worsening peripheral neuropathy may require dose adjustment or change in regimen or conversion to subcutaneous use.

1. Bortezomib: Yellow List. Retrieved 12/09/2023 from: https://www.gelbe-liste.de/wirkstoffe/Bortezomib_48310
2. Tan CRC et al (2019) Clinical pharmacokinetics and pharmacodynamics of bortezomib. Clin Pharmacokinet 58:157-168.