Bortezomib Represent a Valuable Therapy for Multiple Myeloma

Multiple myeloma is the second most common blood cancer and accounts for 154,000 cases and 101,000 deaths per year, worldwide. The global burden of multiple myeloma has been increasing uniformly for the last 30 years with varied prevalence rates among different countries.

It is a type of blood cancer that is caused by excess production and improper function of plasma cells in the bone marrow. Plasma cells are a type of white blood cells that helps in fighting off infections by making antibodies. Too many plasma cells mass together to form tumours inside the bone marrow and various sites of the body. It also prevents the production of normal blood cells, which leads to low blood counts and impairs immunity.

It is predominant among the elderly population with an average age of onset of 65–70 years but in recent years reported its incidence in both elderly and younger age population. Men are more likely to develop myeloma than women. It usually presents symptoms, which are commonly referred to as CRAB: Increase in blood Calcium or HyperCalcemia, Renal failure, Anemia and Bone damage.

The management of multiple myeloma is focused on reducing the existing disease while controlling several complications including hematologic, bone, and renal associated with the disease. The common treatment options for multiple myeloma includes chemotherapy, autologous stem cell transplantation (ASCT), radiation therapy and medicines to improve bone health.

However, there have been advances in the management of multiple myeloma in recent years, leading to remarkable improvements in survival and better treatment outcomes. This clinical progress in multiple myeloma management is highly attributed to the availability of novel and targeted approaches such as proteasome inhibitors and immunomodulators, such as thalidomide, lenalidomide, and bortezomib. Among these drug classes, the proteasome inhibitors make an important class of anti-myeloma drugs.

Bortezomib is the first proteasome inhibitor that has demonstrated significant clinical response in patients with refractory or rapidly advancing multiple myeloma.

In this blog, we will discuss the:

• Clinical uses of Bortezomib
• Mechanism of action
• Dosage and Administration
• Adverse events
• Warning and Precautions
• Drug Interactions
• Conclusion

Clinical uses of Bortezomib

Bortezomib is approved by the Food and Drug Administration (FDA) for the treatment of multiple myeloma. It has been extensively studied in various clinical trials either in monotherapy and in combination with other agents for the management of multiple myeloma.

Existing NCCN guidelines recommended the use of bortezomib as a front line therapy for previously untreated multiple myeloma, primary therapy for transplant patients and maintenance therapy.

It has shown significant clinical efficacy in:

• Patients with previously untreated myeloma
• Patients with advanced or relapsed myeloma
• Patients with high-risk disease and aggressive myeloma
• Patients who had received high dose chemotherapy
• Patients who had received a stem-cell transplant
• Patients with reduced kidney function and bone disease

It significantly improves the response rate and survival outcome in multiple myeloma patients when combined with other chemotherapeutic agents such as doxorubicin and dexamethasone (Dvd), melphalan, prednisone, lenalidomide, and cyclophosphamide

Mechanism of action

Bortezomib acts by blocking the action of proteasomes present inside the cell. Proteasomes are responsible for the breakdown of proteins involved in the cell cycle, repair, and cell death (apoptosis). Inhibition of proteasomes leads to the buildup of these proteins in cells, causing cell cycle arrest and apoptosis.

Dosage and Administration

Bortezomib is available in an injection form which is either given intravenously (IV) or subcutaneously (SC). The dose of bortezomib indicated for multiple myeloma patients is 1.3 mg/m² administered as a 3-5 bolus IV or SC, given twice a week for 2 weeks, followed by a 10-day rest period in cycles 1-4. This dose is then reduced to once weekly for 2 weeks, followed by a 10-day rest period in cycles 5-9.

Adverse events

• Common adverse events of bortezomib include gastrointestinal problems (diarrhoea, constipation, nausea, vomiting), decreased appetite, peripheral neuropathy, fatigue, thrombocytopenia, neutropenia, neuralgia, leucopenia, skin rashes and anaemia.
• Severe adverse events of bortezomib include cardiac disorders, hepatic events, and tumour lysis syndrome

Warning and Precautions

• Bortezomib can lead to hypersensitivity as it may contain inactive ingredients such as boron, mannitol. So, tell your doctor, if you are allergic to it or you have any other allergies
• Bortezomib can cause neuropathy, so signs of neuropathy should be regularly monitored and if symptoms occur, the dose of bortezomib should be modified or discontinued
• Careful risk-benefit assessment should be done before bortezomib use if patients had preexisting severe neuropathy
• Tell your doctor, if you had a history of hypertension, existing heart disease, hepatic disease, syncope and those who are dehydrated before using bortezomib
• The dose should be reduced or modified in patients with moderate or severe hepatic impairment
• Patients with diabetes and hematologic disorders should be closely monitored for blood glucose levels and complete blood counts respectively
• Anti emetic, anti-diarrheal medications and fluid replacement, should be advised in patients with gastrointestinal side effects and dehydration
• Patients with high tumour burden should be closely monitored
• Women should avoid pregnancy while receiving treatment with bortezomib
• Use of bortezomib is not recommended in pregnant and breastfeeding mothers
• Bortezomib can cause dizziness, so do not drive, use machinery, or do anything that needs alertness

Drug Interactions

Drug interactions change the effect of a medication or can increase the risk of side effects associated with it. Research studies have demonstrated that co-administration with strong CYP3A4 inhibitors such as ketoconazole and ritonavir can increase the exposure of bortezomib whereas co-administration with strong CYP3A4 inducers such as rifampin can decrease the exposure of bortezomib. Therefore, the patients should keep a list of prescription and non-prescription drugs they are using and share with their doctor or physician.

Conclusion

Multiple myeloma is not curable but it is treatable with the use of chemotherapy and surgery. Proper diagnosis and effective treatment can significantly prolong the survival rates of patients.

Besides proper management, there is a need to adopt some lifestyle measures. Lifestyle measures do not prevent or cure multiple myeloma but it can boost overall health and improve the quality of life of patients suffering from multiple myeloma.

Adopting a healthy eating routine while exercising regularly will strengthen your immune system and potentially reduce the impact of multiple myeloma on everyday life.

See Mandatory lifestyle modifications for cancer patients to be adopted after-treatment for more detail.