Bortezomib (Intravenous, Subcutaneous)

In treating cases of multiple myeloma and mantle cell lymphoma, bortezomib is a preferred treatment method, offering patients their best chances for recovery by halting cell death and promoting further cell development.

Overview:

Bortezomib, which was originally manufactured under the name PS-341, is a therapeutic proteasome inhibitor, currently marketed as Velcade via Millennium Pharmaceuticals. This is the first such drug to be tested in humans. Bortezomib contains a boron atom that binds with 26S proteasome and serves as a catalyst to arrest cell development and initiate apoptosis, or cell death. Where a cell is functioning normally, 26S proteasome acts to degrade ubiquitylated proteins, because they have been marked as damaged or unneeded. In these instances, the process marks these cells for destruction.

In cancerous cells, this process is disrupted, because pro-apoptotic proteins such as p53 are prematurely degraded by the proteasome compound. This prevents the destruction of damaged and cancerous cells. Normal forms of cell therapy aimed at treating cancer patients has been problematic, because drugs aimed at inhibiting or destroying cancer cells have typically had the same effect on healthy cells. Bortezomib is distinctive in that the boron atom specifically identifies and affects cancerous cells, instead of indiscriminately attacking all cells within the area. For instance, multiple myeloma is treated with bortezomib by arresting the activation of adhesion molecules, before it can implant plasma cells in the bone marrow.

Conditions treated:

  • Multiple myeloma
  • Mantle cell lymphoma

Type of medicine?

  • Therapeutic proteasome inhibitor

Side Effects:

While the most common side effects are listed below, this is by no means a complete list of all side effects that may occur. If the patient experiences any adverse effects, especially those that occur consistently, at a high rate of frequency, or to a moderate or severe degree, he or she is urged to seek medical advice immediately. The presentation of side effects may indicate an adverse reaction to the drug, including an allergic reaction and may be treatable by the patient’s doctor.

The most commonly observed side effects include:

  • Fatigue
  • Malaise
  • General weakness
  • Diarrhea
  • Nausea
  • Constipation
  • Peripheral neuropathy
  • Vomiting
  • Pyrexia
  • Thrombocytopenia
  • Psychiatric disorders
  • Decreased appetite, which can include anorexia
  • Neutropenia
  • Neuralgia
  • Leukopenia
  • anemia

Gastrointestinal

Common side effects affecting the Gastrointestinal system include nausea, which has affected 64% of patients who were treated with bortezomib. Additionally, 51% of patients developed diarrhea, constipation (43%), and a decrease in appetite (43%). Vomiting was experienced in as many as 36% of cases, while 13% of patients developed dyspepsia.

Patients were diagnosed with grade 3 gastrointestinal events in 18% of cases, which was significantly higher than the 1% of patients experiencing grade 4 gastrointestinal events. Overall, 11% of these gastrointestinal events were considered serious.

Gastrointestinal symptoms that were experienced but not reported with a quantifiable frequency of occurrences are:

  • Ascites
  • Dysphagia
  • Fecal impaction
  • Hemorrhagic gastritis
  • Gastrointestinal hemorrhage
  • Hematemesis
  • Paralytic ileus
  • Large intestinal obstruction
  • Paralytic intestinal obstruction
  • Small intestinal obstruction
  • Large intestinal perforation
  • Stomatitis
  • Melena
  • Gastroenteritis
  • Hemorrhagic duodenitis
  • Peritonitis
  • Oral mucosal petechiae
  • Gastroesophageal reflux
  • Acute pancreatitis

Hematologic

The most common hematologic side effects reported by patients were thrombocytopenia, which presented in 34% of patients, and neutropenia, found in 27% of cases. Also reported most commonly were instances of anemia (23%), lymphopenia (23%), and leukopenia (20%).

Hematologic side effects reported in a low number of cases (0.1% to 1%) consisted of:

  • Lymphadenopathy
  • Febrile neutropenia
  • Pancytopenia
  • Hemolytic anemia
  • Thrombocytopenia purpura

Side effects of unknown frequency:

  • Disseminated intravascular coagulation
  • subdural hematoma
  • pancytopenia
  • hemolytic anemia
  • thrombocytopenia purpura

In cases where thrombocytopenia was observed, it was found to affect the patient with a decreased platelet count through the first 11 days of treatment. The baseline platelet count returned to normal for the latter half of the treatment cycle, days 12 through 21. In 24% of cases, the instances of thrombocytopenia were grade 3, while 5% of patients experienced grade 4 thrombocytopenia.

A rate of 9% of patients experienced grade 3 neutropenia, while grade 4 neutropenia affected 3% of patients.

Nervous System

Peripheral neuropathy was reported in 39% of patients, though 51% of those cases were either improved or alleviated through an adjustment in the dosage. Additionally, those patients who discontinued bortezomib treatment due to developing grade 2 or higher of peripheral neuropathy reported an improved condition or resolution of the symptom altogether in 73% of cases. The same rates of recovery were observed in patients experiencing grade 3, during phase 2 multiple myeloma studies.

Peripheral neuropathy caused by the administering of bortezomib is usually sensory, however motor function peripheral neuropathy may also result. Where patients experience pre-existing symptoms, such as numbness or a pain/burning sensation in the extremities, peripheral neuropathy may significantly worsen with this treatment. Patients should be monitored for an increase of symptoms and their dosage should be adjusted accordingly.

Additional nervous system side effects resulting from bortezomib treatments include paresthesia and dysesthesia, found in 23% of cases, as well as headaches (22%), dysgeusia (13%), dizziness (17%), and anxiety (10%).

In 1% to 10% of cases, patients also experienced peripheral sensory neuropathy and/or tremors.

Less common side effects, occurring in just 0.1% to 1% of cases, included:

  • Cerebrovascular accident
  • Convulsion
  • Syncope
  • Difficulty paying attention
  • Increased agitation
  • Ageusia
  • Somnolence
  • Migraine
  • Jerky movements
  • Postural dizziness
  • Sciatica
  • Post herpetic neuralgia
  • Cognitive dysfunction
  • Mononeuropathy
  • Paresis
  • Restless leg syndrome
  • Speech difficulties
  • Intracranial hemorrhage
  • Paraplegia
  • Subarachnoid hemorrhage
  • Autonomic neuropathy
  • Encephalopathy

Musculoskeletal

26% of patients experienced Arthralgia and/or a pain in the limbs as the most common side effects in this category. Less common, occurring in 14% of cases, patients experienced bone pain, muscle cramps, and myalgia. In 13% of patients, back pain was also reported.

Also reported as common side effects, observed in 1% to 10% of patients, were:

  • Peripheral swelling
  • muscle weakness
  • musculoskeletal pain

In just 0.1% to 1% of instances, these uncommon side effects were reported:

  • Joint stiffness
  • Buttock pain
  • Swelling of the joints
  • Muscle spasms and/or twitching
  • Feeling of heaviness
  • Stiff muscles
  • Swelling
  • Jaw pain

Cardiovascular

Hypotension, which included reports of orthostatic hypotension, was the most commonly reported side effect of bortezomib in this category. Hypotension in these instances was diagnosed as a severity of either grade 1 or grade 2. Instance of grade 3 only occurred in 3% of patients, while under 1% of patients developed grade 4 hypotension.

Less commonly reported side effects include:

  • Aggravated atrial fibrillation
  • Atrial flutter
  • Cardiac amyloidosis
  • Cardiac arrest
  • Congestive cardiac failure
  • Hypertension
  • Myocardial ischemia
  • Myocardial infarction
  • Pericardial effusion
  • Pulmonary edema
  • Angina pectoris
  • Bradycardia
  • Sinus arrest
  • Complete atrioventricular block
  • Pericarditis
  • Torsades de pointes
  • Decreased left ventricular ejection fraction
  • Ventricular tachycardia

Respiratory System

Here, the most common side effects, occurring in 10% of cases or more, included Dyspnea in 22% of patients, cough (20%), upper respiratory tract infection (18%), and lower respiratory tract/lung infection (15%). Also, nasopharyngitis was observed in 14% of patients, while 12% of patients developed pneumonia.

Less common, experienced by 1% to 10% of individuals, are the following side effects:

  • Epistaxis
  • Dyspnea following physical exertion
  • Rhinorrhea
  • Bronchitis
  • Sinusitis

Rarely reported, uncommon side effects of bortezomib treatments, observed in just 0.1% to 1% of patients:

  • Nasal congestion
  • Wheezing
  • Pleural effusion
  • Hoarseness
  • Pain in the chest wall
  • Hypoxia
  • Pulmonary congestion
  • Rhinitis
  • Asthma
  • Hyperventilation
  • Orthopnea
  • Sinus pain
  • Throat tightness
  • Productive cough
  • Respiratory alkalosis
  • Respiratory arrest
  • Tachypnea
  • Pneumococcal
  • Bronchopneumonia
  • Pleural infection
  • Pulmonary edema

Dermatologic

The most common dermatologic side effects reported were Rash (18%) and herpes zoster (12%).

Very rare side effects, occurring in less than 0.01%:

  • Erythematous plaques or nodules on the torso
  • Generalized morbilliform erythema with ulcerations and fever
  • Cutaneous vasculitis
  • Histiocytoid Sweet Syndrome

Ocular

Blurred vision was the most common side effect experienced, observed in 11% of patients. Less common, but experienced in 1% to 10% of cases was eye pain.

Uncommon side effects, which were experienced by patients 0.1% to 1% of the time were:

  • Dry eye
  • conjunctivitis
  • Eye discharge
  • Abnormal vision
  • Eye hemorrhage
  • Photophobia
  • Eye irritation
  • Increased lacrimation
  • Conjunctival hyperemia
  • Blepharitis
  • Eye swelling

Extremely rare side effects, including those reported with unknown frequencies, are:

  • Ophthalmic herpes
  • Conjunctival infection
  • Diplopia
  • Optic neuropathy
  • Blindness

Psychiatric

Peripheral neuropathies were commonly observed in patients submitting to bortezomib treatment with a 50% occurrence rate. Other common side effects were insomnia (18% to 27%), neuralgia (23%), and anxiety (14%). Common side effects, though reported in 10% or fewer cases, were instances of agitation, confusion, and depression.

Uncommon side effects, reported in 0.1% to 1% of cases, were:

  • Delirium
  • Restlessness
  • Mood swings
  • Mental status changes
  • Sleep disorder
  • Irritability
  • Hallucinations
  • Abnormal dreams

Dosage

The dosage for previously untreated mantle cell lymphoma consists of 1.3 mg/m2, administered as a bolus IV injection. The treatment should be given twice a week for two weeks in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone. A 10 day rest period should follow this cycle of dosages.

Additionally, a 72 period should lapse between doses. Patients who don’t respond until six cycles of treatment can be administered two additional cycles for a total of 8 treatment cycles.

In cases where mantle cell lymphoma was previously treated unsuccessfully, the dosage should be 1.3 mg/m2, which can be administered as a bolus IV injection or subcutaneously. Again, the treatment cycle consists of two treatments per week for a two week period, followed by a 10 day rest period. Treatment can extend beyond eight cycles either at the standard rate of treatment or it can be given once a week for four additional weeks.

In treating multiple myeloma, a dose of 1.3 mg/m2 should be administered as a 3 to 5 second bolus IV injection. Alternatively, it can be given subcutaneously. In either instance, the treatment should also include a combination of oral melphalan and oral prednisone. Treatment consists of the aforementioned dosages being administered twice weekly for the first four weeks and once weekly for weeks five through nine.

Similarly, a relapse of multiple myeloma should be treated with 1.3 mg/m2 as a bolus intravenous injection or subcutaneously. The patient should receive the bortezomib therapy twice a week over a two week period with a 72 rest period between doses. Treatment required beyond eight cycles may be given in accordance with the standard cycles or adjusted to one treatment a week for four weeks.

Major Drug Interactions

It’s often difficult to predict how some drugs will interact with other drugs that the patient is taking. For this reason, it’s important for the patient and doctor to discuss all drugs the patient has been taking. While this does include drugs prescribed for other medical conditions, it also includes nonprescription drugs that the individual may be taking. Aside from aspirin, ibuprofen, sleeping pills, or over the counter anti-inflammatory medications, this also includes vitamins, herbal remedies, alcohol use, and the use of narcotics.

Although certainly not a definitive list, below are some of the drugs most commonly known to negatively interact with bortezomib. If the patient is taking any of these medications in particular, he or she should be certain to notify the caregiver immediately.

  • Talimogene Laherparepvec
  • Efalizumab
  • Natalizumab
  • St. John’s Wort
  • Ascorbic Acid (Vitamin C)
  • Domperidone
  • Fingolimod
  • Ocrelizumab
  • Clozapine
  • Deferiprone

Additionally, patients should not change medications during the bortezomib therapy process. This includes stopping other medications or changing dosages of any other drugs without first discussing it with their doctor. Any changes should be done safely, under the guidance of a trained physician.

Warnings

It ‘s important for the patient to discuss his or her past medical history with their doctor, prior to beginning bortezomib therapy. The treatment can have harmful effects on an individual who has had or may currently be experiencing certain medical conditions. Patients are advised to warn their doctor of any allergies, especially where the individual may be allergic to bortezomib, mannitol, or boron.

Additionally, bortezomib may not be an effective treatment or may affect the patient adversely, if he or she has ever experienced any of the following conditions:

  • Diabetes
  • Liver disease
  • Kidney disease, including dialysis treatments
  • Bleeding or blood clotting disorders
  • Low blood levels (platelets, white blood cells, or red blood cells)
  • Heart disease
  • Congestive heart failure
  • Lung disease
  • Breathing problems
  • Herpes
  • Shingles
  • Abnormal blood pressure (high or low)
  • Nerve problems (numbness, burning, pain, or tingly feeling)

Additionally, bortezomib therapy should not be administered to pregnant women and patients who are either pregnant or trying to get pregnant should notify their doctor immediately. In laboratory studies on animals, bortezomib cause embryo and fetal death, even when given a dosage lower than that recommended for human treatments. The U.S. Food and Drug Administration has rated bortezomib as a pregnancy category D drug, which means there was evidence of human fetal risk through investigative or marketing experience. However, the rating also recognizes that the potential benefits of administering bortezomib to pregnant women may outweigh the potential risks to the fetus.

In breastfeeding, no evidence has been found in either human or animal tests that the drug was excreted in breast milk. However, the bortezomib manufacturer recommends discontinuing the practice of breastfeeding, while the mother is being treated. Ultimately, this is a decision the pregnant patient and attending doctor should discuss together.

Storage

Bortezomib, manufactured as Velcade by Millennium Pharmaceuticals, is delivered in cartons that contain 10 mL (34 fluid ounce) vials. Each vial contains 3.5 mg of bortezomib in a powder or cake powder form. The unopened vials can be typically stored at room temperature (25ºC/77ºF). When necessary, the vials can be briefly stored in temperatures ranging from 15 to 30ºC (59 to 86ºF).

As bortezomib is administered intravenously by a trained caregiver, it will most often be stored in a hospital setting. For that reason, patients generally won’t need to concern themselves with storing the drug. In the event that home administration of the treatment is arranged, the doctor should educate the patient on appropriate storage procedures. This includes ensuring the patient has adequate equipment for storing bortezomib according to manufacturer specifications.

Gloves and other protective equipment should be worn, whenever handling or disposing of bortezomib. Skin contact should always be avoided.

Summary

Bortezomib is the best treatment for multiple myeloma and mantle cell lymphoma in many cases, even when considering the possible side effects. By following the doctor’s instructions as strictly as possible, the patient can achieve the best possible results from submitting to the treatment procedure. Additionally, as bortezomib can cause drowsiness, the patient is urged to refrain from operating heavy equipment or driving motor vehicles, while following the course of treatment. Dehydration can also be a problem, so patients are recommended to drink three to four quarts of fluid each day, unless that advice contradicts the instructions given to them by their doctor.

As bortezomib can also increase the risk of infection, patients are urged to restrict their physical activities. Contact sports and high endurance physical exercise should not be pursued, during the treatment cycle, and the patient should report any cold, flu, or other illness to their doctor without delay. A healthy diet and a good sleep schedule can help to reduce the side effects of bortezomib, as well.

As diarrhea can be a problematic side effect, patients are also urged to continue regular bowel movements and report incidents of diarrhea to their doctor. The physician may be able to recommend dietary changes or prescribe medication that can reduce or eliminate incidences of diarrhea.

Likewise, by reporting all side effects to their doctor, the patient may be able to receive treatment to reduce the frequency or severity of adverse effects. The doctor may be able to prescribe medication or suggest new lifestyle changes to reduce or eliminate the side effects, as they occur. By working together, the doctor and patient can reduce the adverse reactions caused by bortezomib, while maximizing the effectiveness of the treatment.