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A - Regimen Name

BORT(MNT) Regimen
BORT(MNT)


Disease Site
Hematologic - Multiple Myeloma

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the maintenance treatment of multiple myeloma following autologous stem cell transplant (ASCT). In the clinical trial, patients were eligible for bortezomib maintenance if they previously received bortezomib as part of induction prior to ASCT. Approval was based on an improvement in progression-free survival.

 
B - Drug Regimen

bortezomib
1.3 mg /m² Subcut Day 1
(This drug is not currently publicly funded for this regimen and intent)
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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Starting 3 to 4 months post-ASCT for up to 2 years unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low

  • Patients at risk of tumour lysis syndrome (i.e. high tumour burden) should have appropriate prophylaxis and be monitored closely.

  • Consider the use of antiviral prophylaxis against herpes zoster (shingles) during bortezomib therapy.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

Dosage with toxicity

Dose Level Bortezomib Dose (mg/m2)
0 1.3
-1 1
-2 0.7

Dexamethasone doses may be reduced for dexamethasone-related adverse events (i.e. hypertension, hyperglycemia, fluid retention) to improve tolerability.

 
Table A: Dose Modifications for Hematological and Non-Hematological Toxicities:
 
Toxicity Grade Bortezomib Dose
ANC <0.5 x 109/L Hold+ until recovery; restart at 1 dose level ↓.
Platelets < 25 x 109/L
Drug-related fluid retention* Grade 2 Continue at 1 dose level ↓.
≥ Grade 3 Discontinue.
Non-hematologic toxicity (see table D for neurotoxicity) ≥ Grade 3

Hold+ until ≤ grade 1 or baseline; restart at 1 dose level ↓.

Consider discontinuing for grade 4.

Pneumonitis   Hold and investigate; discontinue if confirmed.
PRES/ PML/ or dose-limiting toxicity at 0.7 mg/m2 Any Discontinue.

+ If no recovery after delay, discontinue.

*Used in mantle cell lymphoma trial by Belch et al.

 

Table B: Dosage for Neurotoxicity
 

Severity of Peripheral Neuropathy Bortezomib Dosage and Regimen Modification
Grade 1 (paresthesia, weakness and/or loss of reflexes) without pain or loss of function No action.
Grade 1 with pain or grade 2 (interfering with function but not with activities of daily living) Restart at 1 dose level ↓.
Grade 2 with pain or grade 3 (interfering with activities of daily living) Hold until toxicity resolves; restart at 2 dose level ↓ (0.7mg/m2 ) and give once per week.
Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life-threatening or leads to paralysis, and/or severe autonomic neuropathy) Discontinue.



Hepatic Impairment

Bortezomib is metabolized by liver enzymes and exposure is increased in patients with moderate to severe hepatic impairment.  Patients with hepatic impairment should be treated with extreme caution and should be closely monitored for toxicities, and dose reduction should be considered.

Suggested dose modifications:

Bilirubin

AST

Starting Dose

≤ 1 x ULN

> ULN

No change

> 1 – 1.5 x ULN

Any

No change

> 1.5 – 3 x ULN

Any

 

First cycle: ↓ to 0.7mg/m2.

Subsequent cycles: Consider ↑ dose to 1mg/m2 or further ↓ dose to 0.5 mg/m2 based on patient tolerability.

> 3 x ULN

Any


Renal Impairment

Dose adjustments are not necessary in patients with renal insufficiency.(Dimopolous 2010) Patients with compromised renal function should be monitored carefully when treated with bortezomib, especially if creatinine clearance is less than 30mL/min.  Bortezomib should be given after dialysis.


Dosage in the Elderly

No dose adjustment is necessary.


 
F - Adverse Effects

Refer to bortezomib drug monograph(s) for additional details of adverse effects.


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Fatigue
  • Diarrhea
  • Nausea, vomiting
  • Constipation (may be severe)
  • Neuropathy (may be severe)
  • Fever
  • Myelosuppression +/- infection (including opportunistic, viral re-activation), bleeding (may be severe)
  • Anorexia, weight loss
  • Headache
  • Cough, dyspnea (may be severe)
  • Musculoskeletal pain
  • Rash (may be severe)
  • Insomnia
  • Edema (may be severe)
  • Abdominal pain
  • Dizziness
  • Abnormal electrolyte(s) (K, Mg, Ca, Na, PO4)
  • Hypotension (may be severe)
  • Rigors
  • Blurred vision
  • Dyspepsia
  • Cardiotoxicity
  • Arrhythmia
  • QTc prolongation
  • Arterial/venous thromboembolism
  • Pericarditis
  • Tumour lysis syndrome
  • Disseminated intravascular coagulation
  • Hemolytic uremic syndrome
  • GI obstruction, perforation
  • Pancreatitis
  • Hepatotoxicity
  • Nephrotoxicity
  • Nephrotic syndrome
  • Hypersensitivity
  • Pulmonary hypertension
  • PML
  • PRES/PRLS
  • Optic neuritis
  • Seizure
  • Graft loss
  • Sudden death (with induction)

 

 

 
G - Interactions

Refer to bortezomib drug monograph(s) for additional details


  • Avoid co-administration with strong CYP3A4 inducers; monitor closely for toxicity if co-administered with CYP3A4 inhibitors.

  • Avoid green tea and preparations containing green tea.

  • Avoid vitamin C supplementation.

  • Exercise caution and monitor blood glucose when co-administered with hypoglycemic agents.

  • Exercise caution and monitor with drugs associated with neuropathy or hypotension.

 
H - Drug Administration and Special Precautions

Refer to bortezomib drug monograph(s) for additional details


Administration

  • Bortezomib may be administered:

    • Intravenously (1 mg/mL concentration) as a 3 to 5 second bolus injection or

    • Subcutaneous (2.5 mg/mL concentration)

  • Bortezomib should only be reconstituted with 0.9% sodium chloride injection.

  • Bortezomib is FATAL IF GIVEN INTRATHECALLY.

  • Bortezomib has a narrow therapeutic range. If a different reconstituted concentration is used for each route of administration, exercise caution when reconstituting and calculating the dose volume.

  • If local injection site reactions occur following subcutaneous bortezomib, consider using a less concentrated solution subcutaneously (1 mg/mL), or administer as IV.

  • For subcutaneous use, bortezomib solution is injected into the right or left sides of the thighs or abdomen. Rotate injection sites with subsequent injections. Give new injections at least 2.5 cm from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.

  • Unopened vials may be stored between 15 and 30º C. Retain in original package and protect from light.

 

Contraindications

  • Patients with hypersensitivity to bortezomib, boron, mannitol, or other excipients

  • Bortezomib is NOT for intrathecal use. Fatal if given intrathecally. 

 

Warning and Precautions

  • Caution should be exercised when driving or using machinery, and in patients on medication(s) that may lead to hypotension, or patients with dehydration or history of syncope, due to the risk of hypotension and dizziness.

  • Use with caution in patients with amyloidosis or risk factors for seizures.

  • Use with caution in patients with risk factors for or existing cardiac disease.

  • Use with caution in patients with pre-existing peripheral or autonomic neuropathy; patients with pre-existing severe neuropathy should be treated with bortezomib only after careful risk/benefit assessment.

 

Pregnancy and Lactation

  • Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib. Adequate contraception should be used by both genders during bortezomib treatment and for 3 months after treatment completion.

  • Breastfeeding is not recommended.

  • Fertility effects: Probable

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • Blood glucose levels, especially in patients using antidiabetic medications and those receiving dexamethasone; baseline and as clinically indicated

  • CBC; Baseline and as clinically indicated (at minimum, prior to each cycle); monitor platelets before each dose

  • Chest X-ray; baseline, then Chest X-ray and lung function assessment if ILD is suspected

  • Liver and renal function tests, electrolytes; baseline, at each cycle and as clinically indicated

  • Clinical toxicity assessment of fatigue, hypotension, neurotoxicity, infection, bleeding, respiratory symptoms, tumour lysis syndrome, cardiovascular, skin, neurologic and GI side effects; at each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • LVEF monitoring in patients with cardiac risk factors; baseline and as clinically indicated

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J - Administrative Information

Approximate Patient Visit
0.5 hour
Pharmacy Workload (average time per visit)
16.369 minutes
Nursing Workload (average time per visit)
27.500 minutes
 
K - References

Bortezomib drug monograph, Cancer Care Ontario.

Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55.
 


July 2019 Updated monograph format, Adverse Effects, Pregnancy and Lactation and Monitoring sections; added PEBC guideline link


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
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