CYBORP

REPEAT EVERY 28 DAYS

Until disease progression or unacceptable toxicity

Other Supportive Care:

• Oral hydration is encouraged to prevent dose-related hemorrhagic cystitis.

• Strongly consider antiviral prophylaxis for herpes zoster
• Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely

Also refer to CCO Antiemetic Recommendations.

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Suggested dose levels:

Hematologic toxicities (Table A):

_{*Restart treatment if platelets ≥ 50 x 10⁹/L, ANC ≥ 1 x 10⁹/L, toxicities recovered to ≤ grade 2 (or as defined in table B).
^# since last dose – for example if day 1, would be since last cycle; or if on D8, would be since day 1}

Non-hematologic toxicities (Table B):

^_{Patients with symptoms of pneumonitis/ARDS should have all drugs held, be appropriately investigated and managed; if diagnosis is confirmed, permanently discontinue.}

Patients with pre-existing severe neuropathy should be treated with bortezomib only after careful risk/benefit assessment. Dose reductions are not required for cyclophosphamide or prednisone.

Dosage for Neurotoxicity (Table C)

No dosage adjustment required for prednisone.

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, should be closely monitored for toxicities, and dose reduction should be considered.

No dosage adjustment required for prednisone.

No dose modification routinely required for cyclophosphamide, but should be used with caution.  There is no evidence to suggest that bortezomib dosage adjustments are necessary in elderly patients.

Refer to cyclophosphamide, bortezomib, dexamethasone drug monograph(s) for additional details of adverse effects

Refer to cyclophosphamide, bortezomib, prednisone drug monograph(s) for additional details

• Exercise caution and monitor blood glucose when co-administered with hypoglycemic agents 
• Avoid co-administration with strong CYP3A4 inhibitors and inducers. If co-administered with CYP3A4 inhibitors, monitor closely for toxicity.  Avoid grapefruit juice 48 hours before and on the day of receiving cyclophosphamide.
• Caution and monitor with drugs associated with neuropathy, hypotension, cardiotoxicity, nephrotoxicity, hepatotoxicity, pulmonary toxicity, thromboembolism (additive effects)
• Avoid green tea and preparations containing green tea during bortezomib treatment given potential for reduced efficacy.
• Avoid vitamin C supplementation during bortezomib treatment given potential for reduced efficacy. If must give, suggest vitamin C up to 500 mg  given 12 hours before or after bortezomib dose.
• Use with caution with allopurinol, thiazide diuretics and ACE inhibitors as increased myelosuppression with cyclophosphamide has been reported.
• Avoid concomitant use of cyclophosphamide and lovastatin, as increased rhabomyolysis has been reported.
• Prolonged post-operative apnea may occur with depolarizing muscle relaxants (e.g. succinylcholine). Notify anesthesiologist prior to use; succinylcholine dose modification may be required.
• Cyclophosphamide may decrease absorption of digoxin and verapamil; monitor for reduced drug effects

Refer to cyclophosphamide, bortezomib, prednisone drug monograph(s) for additional details

Administration

Cyclohosphamide:

• Oral hydration is strongly encouraged; for PO cyclophosphamide: 8-10 (8oz) glasses of fluid per day. Inadequate total hydration may result in dose-related hemorrhagic cystitis.  Patients should be encouraged to empty their bladder frequently to minimize dwell times. 
•  Oral tablets should be administered as a single dose in the morning, with or without food.
• Store in the original packaging at room temperature, away from heat, light or moisture

Bortezomib:

• Bortezomib should be administered via intravenous or subcutaneous routes only.
• 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.
• The Canadian product monograph recommends the following concentrations to be used for injections:  ► Intravenous:  1 mg/mL; ► Subcutaneous:  2.5 mg/mL
• Some centres have routinely used the bortezomib 1mg/mL concentration for all subcutaneous injections.
• If local injection site reactions occur following subcutaneous bortezomib, consider using a less concentrated solution subcutaneously (1 mg/mL), or administer as IV.                  
• IV: Administered as a 3 to 5 second IV push through a peripheral or central IV catheter, followed by a standard saline flush; no central line is required.
• 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.

Prednisone:

• oral self-administration
• give tablets with food, preferably in the morning

Contraindications:

• patients with severe hepatic or renal impairment• patients with severe myelosuppression and/or immunosuppression
• patients who have a hypersensitivity to bortezomib or cyclophosphamide or any of its components
• patients with active infection, particularly varicella zoster infection

Other Warnings/Precautions:

• patients with urinary outflow obstruction
• patients with adrenal insufficiency
• in combination with neuromuscular blockers
• Avoid live or live-attenuated vaccines as use may result in serious or fatal infections in immunocompromised patients. Reduced immunogenicity may occur with use of inactivated vaccines.
• 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.

Pregnancy and lactation:

• Cyclophosphamide is mutagenic, carcinogenic, genotoxic, teratogenic and fetotoxic in humans. Testicular atrophy and sterility may occur in males. Sperm-banking before treatment should be considered. Amenorrhea and ovarian failure may occur in females. Gonadal dysfunction may reverse with time, but future reproductive capacity is uncertain.  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.

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

Suggested Clinical Monitoring

Cyclophosphamide and Prednisone:  Outpatient prescription for home administration

Bortezomib and cyclophosphamide drug monographs, Cancer Care Ontario

CYBORD Regimen monograph, Cancer Care Ontario.

Reece DE, Rodriguez GP, Chen C, et al.  Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma.  J Clin Oncol 2008;26(29):4777-83.

• Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline