Bortezomib for AL Amyloidosis - A Complete Guide

Overview:

Bortezomib is a proteasome inhibitor that has been used to manage several medical conditions, including light-chain amyloidosis also known as AL amyloidosis. Bortezomib is either used alone or in combination with drugs like Daratumumab, Hyaluronidase, Dexamethasone, Melphalan, or Cyclophosphamide. Bortezomib got approval from the United States Food and Drug Administration (US FDA) in May 2003 for treating multiple myeloma (plasma cell cancer). However, the use of Bortezomib with Daratumumab and Hyaluronidase for treating AL amyloidosis was approved only on January 15th, 2021.

Dosage and Route of Administration:

The regimen that is suggested for treating light chain amyloidosis is a combination of Daratumumab and Hyaluronidase along with Bortezomib, Dexamethasone, and Cyclophosphamide. The dosage and administration route of this Bortezomib regimen is as follows:

• Bortezomib is administered through subcutaneous injection over the stomach or thighs. The dosage will be 1.3 mg/m² (milligrams per square meter). The Bortezomib subcutaneous injection will be given twice a week in a 21-day cycle. Depending on the response of the patient to the Bortezomib regimen, the number of cycles of this regimen may vary. However, the commonly employed number of cycles is six to eight.

• Cyclophosphamide with a dose of 300 mg/m2 will be given on the days one, eight, and 15 of this 21-day cycle.

• This regimen includes 20 milligrams (mg) of Dexamethasone given through the oral route. It will be taken on the day of the Bortezomib subcutaneous injection and the next day.

• Daratumumab and Hyaluronidase-containing injections will be given subcutaneously. This injection will be given once in the first eight weeks, followed by one injection every two weeks from week nine to 24. From the 25th week, the Daratumumab and Hyaluronidase injection will be given once every four weeks till the disease progression is curbed. The administering dosage of Daratumumab is 1800 mg, and Hyaluronidase is 30,000 units.

For Patients:

What Is Light Chain (AL) Amyloidosis?

Light chain (AL) amyloidosis is considered a primary form of amyloidosis, causing systemic manifestations in the affected individuals. In this type of amyloidosis, the plasma cells produce immunoglobulin light chains, which are abnormal and insoluble protein fibrils. This pathological production and accumulation of light chains occur throughout the body without disintegrating, thus resulting in the incidence of AL amyloidosis. What causes such immunoglobulin light chains to accumulate is yet to be determined. However, studies show that the presence of underlying plasma cell disorders like multiple myeloma or monoclonal gammopathy (presence of abnormal pathological antibodies in the body) can trigger the buildup of abnormal light chain amyloid fibrils in important tissues and organs.

What Are the Symptoms of Light Chain Amyloidosis?

Due to the deposition of amyloids in vital organs, people may have clinical manifestations through various systems in the body, such as:

• Difficulty breathing.

• Fatigue.

• Swelling of legs and ankles (Pedal edema).

• Difficulty lying down flat (as a result of fluid buildup).

• Irregular heartbeats.

• Palpitations.

• Frequent fainting episodes.

• Foamy urine (indicating protein elimination in urine).

• Fluid retention causes excessive weight gain suddenly.

• Decreased urinary output.

• Generalized fatigue.

• Confusion.

• Abdominal pain (due to an enlarged liver).

• Alternating episodes of loose motions and constipation.

• Generalized malaise.

• Reduced energy to perform routine activities.

• Sudden weight loss.

• Enlarged tongue.

• Hemorrhagic spots (specifically under the eyes and oral cavity).

Why Is Bortezomib Regimen Given for Treating AL Amyloidosis?

The Bortezomib regimen helps to inhibit the action of proteasome enzymes. Proteasome enzymes are important cellular components that recycle and degrade pathologically formed light chains by the plasma cells. In the context of AL amyloidosis, the proteasome's normal function is disrupted due to the overproduction of immunoglobulin light chains by clonal plasma cells. These light chains, instead of being efficiently degraded, misfold and escape the usual proteasomal degradation pathway. This results in amyloid fibrils formation and tends to accumulate all over the vital organs.

Bortezomib works by disrupting such a proteasome's function, thereby inducing cell death of the abnormal plasma cells. This reduction in light chain production can lead to a decrease in amyloid deposits and result in stabilization or improvement of organ function.

Along with Bortezomib, the regimen contains Daratumumab to target CD38 present in the plasma cells for killing the plasma cells. Hyaluronidase is given along with Daratumumab for better absorption of Daratumumab when given subcutaneously. Cyclophosphamide works synergistically with Bortezomib by alkylating the plasma cells, helping destroy them, and inhibiting amyloid production. Dexamethasone exerts an anti-inflammatory effect to subside the inflammatory process that is seen in amyloidosis.

How Should the Bortezomib Regimen Be Taken?

Bortezomib and Daratumumab (with Hyaluronidase) will be given subcutaneously in the abdomen or thigh, and the dosing cycles will be determined by the physicians who prescribe them.

Cyclophosphamide can be given as an oral or injectable form. When given through an oral route, people taking Cyclophosphamide will be asked to drink hefty amounts of water.

Dexamethasone will be given through the oral route, and patients will be asked to take it on the day of injection and the subsequent day to reduce the incidence of inflammation secondary to subcutaneous injections.

Missed Bortezomib Dose:

A missed complete regimen of Bortezomib and Daratumumab (with Hyaluronidase) should be taken immediately when remembered, or the missed dose should be adjusted as per the dosing schedule.

What Are the Side Effects of Taking Bortezomib Regimen for AL Amyloidosis?

The most common side effect of taking Bortezomib along with Daratumumab and Hyaluronidase is cardiac toxicity. There can also be aggravation of symptoms if people have pre-existing cardiac diseases.

Other side effects of the Bortezomib regimen include:

• Injection site reactions.

• Rashes.

• Inflammation.

• Upper respiratory tract infection.

• Pneumonia (inflamed air sacs).

• Constipation.

• Nausea.

• Fever.

• Reduced neutrophil count.

• Reduced platelet count.

• Abdominal pain.

• Generalized fatigue.

• Swelling in the lower limbs.

• Damaged peripheral nerves (peripheral neuropathy).

• Numbness.

• Tingling sensation in extremities.

• Dizziness.

• Cough.

• Sleep disturbance.

• Back pain.

• Muscle pain.

• Reduced appetite.

• Urinary tract infection.

• Joint pain.

• Reduced calcium levels in blood.

• Difficulty breathing.

• Reduced hemoglobin levels.

• Sudden fainting.

• Vomiting.

• Dehydration.

• Sudden infection with Herpes virus (which manifests as vesicles in the trunk area).

What Are the Precautions to Be Taken Before Taking a Bortezomib Regimen?

• Bortezomib regimen with Daratumumab, Hyaluronidase, and Cyclophosphamide for treating AL amyloidosis tends to cause nervous damage, specifically to the peripheral nerves. So, people who have nervous disorders are not advised for a combination regimen with Bortezomib for AL amyloidosis.

• An unexpected dip in blood pressure can happen soon after the administration of the Bortezomib regimen.

• There is an elevated susceptibility for bacterial infections causing upper respiratory and urinary tract infections and viral infections like Herpes. Hence, appropriate medicines and antibiotics should be taken before starting the Bortezomib regimen.

• People with existing heart diseases can experience an exaggeration in cardiac symptoms after taking a Bortezomib regimen. The most common manifestations seen are atrial fibrillation (irregular atrial beating) and cardiac failure. So, such patients are contraindicated for treatment with the Bortezomib regimen.

• Taking Bortezomib along with Daratumumab can cause profuse vomiting in some patients. Taking antiemetics in such cases is necessary.

• Lysed tumor cells following the administration of Bortezomib can cause tumor lysis syndrome, which manifests as reduced calcium levels and increased potassium and phosphate levels in the blood.

For Doctors:

Clinical Pharmacology:

Bortezomib disrupts the protein degradation pathway in plasma cells, leading to reduced abnormal protein (amyloid) production. Daratumumab aids in the destruction of malignant plasma cells (by targeting CD38). Cyclophosphamide interferes with DNA replication and cell division of the aberrant plasma cells. Together, combination therapy with Bortezomib, Daratumumab, Hyaluronidase, Dexamethasone, and Cyclophosphamide aims to suppress the production of amyloidogenic proteins and reduce the burden of abnormal plasma cells.

Indications:

• A combination regimen of Bortezomib, Daratumumab, Hyaluronidase, Dexamethasone, and Cyclophosphamide is given to treat AL amyloidosis.

• Multiple myeloma patients.

• Patients with mantle cell lymphoma.

• A combination regimen is also given to people who have undergone autologous stem cell transplants.

Contraindications:

• Pregnant ladies.

• Pre-existing cardiac diseases.

• Pre-existing nerve disorders.

• Hypersensitivity to components of the combination injection.

Half-Life:

The half-life of Bortezomib is around 15 hours, and Daratumumab is approximately 28 days.

Pharmacokinetics:

Absorption:

The peak concentration of the combination regimen is reached in around four days of administration. Hyaluronidase is administered with Daratumumab in this combination regimen to enhance the absorption process.

Distribution:

Bortezomib binds to plasma proteins and distributes through the systemic circulation. Daratumumab has limited penetration into the tissues (owing to its large molecular size).

Metabolism:

Bortezomib undergoes metabolism in the liver with cytochrome enzymes followed by proteasomal degradation. The proteolytic enzymes also help in the metabolism of Daratumumab and Cyclophosphamide, which are administered in the combination regimen. Cyclophosphamide’s metabolism forms metabolites like 4-hydroxycyclophosphamide and aldophosphamide.

Elimination:

83 percent of the unchanged drug of Bortezomib is eliminated through feces and urine within 11 days of administration. The elimination process of Daratumumab takes around 28 days, and it is cleared by the reticuloendothelial system. Within 12 hours, Cyclophosphamide will also be eliminated.

How to Administer Bortezomib Regimen for AL Amyloidosis Treatment?

• Till the combination regimen is administered, Bortezomib can be safely kept at normal room temperature (25 degrees Celsius/ 77 degrees Fahreinheit), and Daratumumab-Hyaluronidase vials should be stored in the refrigerator (two degrees Celsius/ 35.6 degrees Fahreinheit). Bortezomib is often administered intravenously at a dose of 1.3 mg/m² over three to five seconds, with treatment cycles typically lasting 21 or 28 days. Subcutaneous administration is an alternative option with the same dose but with a longer infusion time of three to five minutes.

• 15 mL (milliliters) of the prepared dose of Daratumumab-Hyaluronidase combination will be injected subcutaneously in the abdomen (three inches left or right of the navel) for a time period of three to five minutes.

• Dexamethasone and Cyclophosphamide are generally prescribed for oral administration.

Drug Interactions:

• Bortezomib is metabolized by CYP3A4/5 and CYP2C19 enzymes, and its plasma levels can be significantly affected by drugs that interact with these enzymatic pathways. Strong CYP3A4/5 and CYP2C19 inhibitors (like Ketoconazole) can increase Bortezomib plasma levels, potentially enhancing its toxicity. On the other hand, strong CYP3A4/5 inducers (like Carbamazepine) can decrease Bortezomib plasma levels.

• People under a Bortezomib regimen are also not advisable for Hypericum perforatum as the levels of Bortezomib go extremely low after concurrent administration.

• Daratumumab, used in the regimen for treating AL amyloidosis, is known to bind to CD38 on the erythrocytes. This usually gives a false positive result in Coomb’s test.

• Daratumumab, when administered along with other immunosuppressants, can reduce immune actions and can increase the susceptibility of amyloidosis patients to acquire infections easily.

• Cyclophosphamide, when given along with anticoagulants, can enhance the anticoagulatory action of AL amyloidosis patients, increasing their susceptibility to spontaneous bleeding.

• Cyclophosphamide with Allopurinol can cause severe suppression of the bone marrow (this can result in aplastic anemia).

Guidelines for Specific Population:

Pregnancy and Lactating Mothers:

The combination of Bortezomib with Daratumumab, Hyaluronidase, Cyclophosphamide, and Dexamethasone for treating AL amyloidosis is known to cause severe harm to the fetus, and hence pregnant ladies are not indicated for a Bortezomib regimen. Major birth defects or miscarriages are commonly associated with the Bortezomib regimen. This is because immunoglobulin (Daratumumab) in the regimen can cross the placenta and, in turn, cause an excessive reduction in fetal CD38 cells. Thus, the immune response of the developing fetus is reduced. Reduced bone density in the fetus is also noted after Daratumumab administration.

There is no data regarding the presence of Bortezomib and the combination drugs in human breast milk. However, the regimen is not indicated for breastfeeding mothers affected by AL amyloidosis. Women under the Bortezomib regimen are not indicated to breastfeed until two months after the last dose of the cycle.

Contraception:

Women with AL amyloidosis should use effective contraceptive methods when they are under a Bortezomib regimen. This should be continued at least seven months after the last dose of the Bortezomib regimen.

Males taking the Bortezomib regimen also should employ contraceptive methods at least up to four months after the last injection of the Bortezomib combination regimen.

Geriatric Population:

There is no change in the pharmacokinetic process in the geriatric population under the Bortezomib regimen for AL amyloidosis. However, geriatric people are highly susceptible to specific side effects like swelling and edema in the legs, generalized muscular weakness, profound and sudden drop in blood pressure, or inflammatory respiratory disease (pneumonia).

Pediatric Population:

The use of the Bortezomib regimen for treating AL amyloidosis in the pediatric population is not yet established.