Les renseignements du Formulaire de médicaments s’adressent aux professionnels de la santé. Il ne s’agit pas d’un avis médical. Certains des renseignements, y compris ceux sur le financement des médicaments anticancéreux, ne s’appliquent pas à tous les patients. Les plans de traitement du cancer sont propres à chaque patient. Si vous êtes un patient, veuillez parler avec votre équipe soignante pour comprendre comment ces renseignements s’appliquent à vous.
BMP
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.
Previously untreated multiple myeloma patients who are unsuitable for stem cell transplantation
bortezomib
New Drug Funding Program
(Bortezomib - Previously Untreated - Multiple Myeloma)
(NDFP Website)
melphalan
ODB - General Benefit
(melphalan - oral tablets)
(ODB Formulary
)
prednisone
ODB - General Benefit
(prednisone)
(ODB Formulary
)
A: STANDARD REGIMEN 1 - Cycles 1 - 9 (every 5 weeks):
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bortezomib 2 | 1.3 mg /m² | IV / Subcut | Days 1, 8, 15, 22 |
| melphalan | 9 mg /m² | PO | Days 1 to 4 |
| prednisone | 60 mg /m² | PO | Days 1 to 4 |
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bortezomib 2 | 1.3 mg /m² | IV / Subcut | Days 1, 4, 8, 11, 22, 25, 29, 32 |
| melphalan | 9 mg /m² | PO | Days 1 to 4 |
| prednisone | 60 mg /m² | PO | Days 1 to 4 |
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bortezomib 2 | 1.3 mg /m² | IV / Subcut | Days 1, 8, 22, 29 |
| melphalan | 9 mg /m² | PO | Days 1 to 4 |
| prednisone | 60 mg /m² | PO | Days 1 to 4 |
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1Blood 2010;116(23):4745-53. 2Missed doses should not be made up. A minimum of 72 hours is required between bortezomib doses |
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STANDARD REGIMEN:
REPEAT EVERY 5 WEEKS
For a usual total of 9 cycles in the absence of disease progression or unacceptable toxicity
OR ALTERNATIVE REGIMEN:
REPEAT EVERY 6 WEEKS
For a usual total of 9 cycles (4 cycles of initial phase and 5 cycles of maintenance phase) in the absence of disease progression or unacceptable toxicity
Low
No routine prophylaxis for melphalan PO
Other Supportive Care:
- Allopurinol and hydration to reduce the risk of tumour lysis syndrome are recommended, especially for patients with high tumour load.
- Consider antiviral prophylaxis (ie. acyclovir) for herpes zoster.
Also refer to CCO Antiemetic Recommendations.
Doses should be modified according to the protocol by which the patient is being treated. The following recommendations are in use at some centres.
Dosage with toxicity
(Continued on next page)
Dose Modifications for Hematological and Non-Hematological Toxicities:
Patients with symptoms of pneumonitis or ARDS should have treatment withheld and be appropriately investigated.
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Table B: In Combination with Melphalan and Prednisone
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Dose modification and delay
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Toxicity Prior Cycle / Day 1 of Cycle
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Day 1 AGC < 1 x 109/L or platelets < 70 x 109/L
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Delay until recovery
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Grade 4 AGC or platelets ≥ 5 days or febrile neutropenia or thrombocytopenic bleeding PRIOR cycle
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Reduce melphalan dose by 25%
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Bortezomib held (≥ 3 times in a cycle during twice weekly administration, or ≥ 2 times in a cycle during weekly administration)
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Reduce bortezomib by 1 dose level
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Grade 3 or 4 non-hematologic toxicity (see table B for neurotoxicity)
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Hold until ≤ grade 1/baseline then restart with 1 dose level ↓. Consider discontinuing for grade 4.
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| Any grade RPLS/ PML/ pneumonitis or dose-limiting toxicity at 0.7 mg/m2 | Discontinue |
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Toxicity During Cycle
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ANC ≤ 0.75 x 109/L or platelet ≤ 30 x 109/L
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Hold both bortezomib and melphalan (if applicable)
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Grade 3 or 4 non-hematologic toxicity (see table B for neurotoxicity)
|
Hold until ≤ grade 1/baseline then restart with 1 dose level ↓. Consider discontinuing for grade 4.
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| Any grade RPLS/ PML/ pneumonitis or dose-limiting toxicity at 0.7 mg/m2 | Discontinue |
Dosage for Neurotoxicity: Patients with pre-existing severe neuropathy should be treated with bortezomib only after careful risk/benefit assessment.
(Continued on next page)
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Table B: Severity of Peripheral Neuropathy |
Bortezomib Dosage and Regimen Modification |
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Grade 1 (paresthesias and/or loss of reflexes) without pain or loss of function |
No action |
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Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living) |
Reduce dose to 1 mg/m2 |
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Grade 2 with pain or Grade 3 (interfering with activities of daily living) |
Hold bortezomib until toxicity resolves. When toxicity resolves, reinitiate at a reduced dose of 0.7mg/m2 and give once per week. |
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Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life-threatening or leads to paralysis) |
Discontinue permanently |
Hepatic Impairment
Melphalan: No adjustment required
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 |
Bortezomib 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 0.5mg/m2 based on patient tolerability. |
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> 3 x ULN |
Any |
Renal Impairment
Bortezomib: Dose adjustments are not necessary in patients with renal insufficiency.† 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.† (†Information obtained from bortezomib US prescribing information, January 2012)
Melphalan: Increased incidence of severe myelosuppression has been observed in patients with BUN ≥ 10.7 mmol/L. Dose reduction should be considered in patients with renal insufficiency receiving melphalan.
| Creatinine clearance (mL/min) | % Melphalan usual dose |
| 10-50 | 75% and monitor |
| <10 | 50% and monitor |
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Most Common Side Effects
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Less Common Side Effects, but may be |
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Recommended Clinical Monitoring
- Blood glucose levels, especially in patients using antidiabetic medications
- CBC; at each visit
- CXR; baseline
- CXR and lung function assessment, if ILD is suspected
- Liver and renal function tests, electrolytes; baseline and regular
- Routine toxicity ratings of fatigue, neuropathy, infection, bleeding, respiratory symptoms, tumour lysis syndrome, muscle weakness, ophthalmic, cardiovascular 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
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Brinjhen S, Larocca A, Rossi D, et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010; 116(23);4745-4753.
Channan-Khan A, Sonneveld P, Schuster MW et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol 2008; 26: 4784-90.
Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncology 2011;12:431-40.
San Miguel JF, Schlag R, Nuriet K, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM 2008; 359: 906-17.
May 2019 Updated emetic risk category; added PEBC guideline link
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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.