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BORTDEXADARA

Cancer Type: Hematologic, Multiple Myeloma  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Bortezomib - Relapsed or Refractory Multiple Myeloma
New Drug Funding Program
    Daratumumab – In Combination with Bortezomib and Dexamethasone for Relapsed Multiple Myeloma
ODB - General Benefit
    dexamethasone
A - Regimen Name

BORTDEXADARA Regimen
Bortezomib-Dexamethasone-Daratumumab


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 treatment of patients with relapsed or refractory multiple myeloma who have received one or more prior lines of therapy. 

 


Supplementary Public Funding

bortezomib
New Drug Funding Program (Bortezomib - Relapsed or Refractory Multiple Myeloma)

daratumumab
New Drug Funding Program (Daratumumab – In Combination with Bortezomib and Dexamethasone for Relapsed Multiple Myeloma)

dexamethasone
ODB - General Benefit (dexamethasone) (ODB Formulary )

 
B - Drug Regimen

Cycles 1 to 3 (Q21 Days):

bortezomib
1.3 mg /m² Subcut Days 1, 4, 8 and 11
daratumumab

*

16** mg /kg IV Days 1, 8 and 15
dexamethasone
20 mg PO Days 1, 2, 4, 5, 8, 9, 11, 12

 


Cycles 4 to 8 (Q21 Days):

 

bortezomib
1.3 mg /m² Subcut Days 1, 4, 8 and 11
daratumumab

*

16 mg /kg IV Day 1
dexamethasone
20 mg PO Days 1, 2, 4, 5, 8, 9, 11, 12

 

 

See DARA(MNT) for Cycles 9 and beyond

 

Alternative Schedule (with bortezomib weekly):

Cycles 1 to 3 (Q21 Days):
 

 

bortezomib
1.3 mg /m² Subcut Days 1, 8, 15
daratumumab

*

16** mg /kg IV Days 1, 8, 15
dexamethasone

40 mg PO Days 1, 8, 15

 

 

Cycles 4 to 8 (Q21 days): 

 

 

bortezomib
1.3 mg /m² Subcut Days 1, 8, 15
daratumumab

*

16 mg /kg IV Day 1
dexamethasone

40 mg PO Days 1, 8, 15

 


See DARA(MNT) for Cycles 9 and beyond

 

*Daratumumab infusion should be administered at the appropriate initial infusion rate with incremental escalation.  Subsequent infusion rate escalation or dilution reduction should only be considered if the previous infusion was well-tolerated.  See the Administration section for details.

**Splitting the first dose over 2 days has been described (8 mg/kg days 1 and 2) and may be considered. The same pre-medications should be administered prior to both treatment days (Reece et al 2018). See Premedication and Supportive Measures section for details. 

Dexamethasone may be given as 20 mg PO on day 1 as daratumumab pre-medication and 20 mg PO on day 2 as daratumumab post-medication.

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C - Cycle Frequency

CYCLES 1 TO 8: EVERY 21 DAYS

Refer to DARA(MNT) for CYCLES 9 AND BEYOND (Daratumumab monotherapy REPEAT EVERY 28 DAYS until disease progression or unacceptable toxicity)

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Low

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Supportive care:

  • Consider antiviral prophylaxis for herpes zoster reactivation

  • Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely
     

Pre-infusion Medications to be administered 1-3 hours prior to daratumumab:

  • corticosteroid (as part of treatment regimen)*

  • antipyretic (acetaminophen 650-1000 mg PO)

  • antihistamine (diphenhydramine 25-50 mg IV / PO, or equivalent)

  • famotidine 20 mg IV (or equivalent)#

  • montelukast 10 mg PO#

*Administer IV prior to the first infusion; oral administration may be considered prior to subsequent infusions.

#These agents were given in addition to above prior to daratumumab infusion in Nooka et. al. The addition of montelukast to first infusion pre-medications significantly reduced the incidence of infusion-related reactions, and numerically reduced the incidence of respiratory infusion-related reactions (Nooka et al. 2018)
 

Post-infusion Medications:

Consider administering:

  • corticosteroids (as part of the treatment regimen)

  • bronchodilators (short and long acting), and inhaled corticosteroids if higher risk of respiratory complications (e.g. COPD, asthma)**

**may be discontinued after the 4th infusion if no major IRRs

 
E - Dose Modifications

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

HBV screening should be performed in all patients prior to starting daratumumab.

Patient's blood should be typed and screened prior to starting daratumumab given the potential for interference with the indirect Coombs test.

Dosage with toxicity

In the clinical trial, dose modifications were not permitted for daratumumab. Doses were held for toxicity as suggested below and missed doses were not made up. Discontinue daratumumab if a dose is delayed by more than 28 days.

For bortezomib, dose reductions were permitted at the following dose levels:

Dose level Bortezomib Dose (mg/m2)
0 1.3
-1
-2 0.7
-3 Discontinue 
 

Table A - Suggested Dose Modifcations:
 
Toxicity Severity Daratumumab dose Bortezomib Dose
Neutropenia Grade 3 without complications No change No change; consider adding G-CSF
  Febrile neutropenia or Grade 4 Hold until ≤ grade 2

Hold until recovery to baseline or ≤ grade 2. Restart at the current dose and consider G-CSF support. 

If recurs, restart at 1 dose level reduction. 

Thrombocytopenia Grade 3 with bleeding or Grade 4 Hold until ≤ grade 2 Hold until recovery to baseline or ≤ grade 2. Restart at 1 dose level reduction. 
Non-hematologic toxicity* Grade 3 or higher Hold until ≤ grade 2 If bortezomib-related, hold until recovery to ≤ grade 2. Restart at 1 dose level reduction.
PRES/PML/pneumonitis/dose limiting bortezomib toxicity at 0.7 mg/m2 dose Any grade n/a Discontinue
HBV reactivation Any

Hold treatment (including steroids). Consult with a HBV expert and manage appropriately.

Restart of treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

*except grade 3 nausea/vomiting/diarrhea that responds to antiemetics/antidiarrheals; grade 3 isolated GGT elevation; grade 3 fatigue present at baseline or that lasts for < 7 days after the last administration of daratumumab; neurotoxicity with bortezomib (see table B); infusion-related reaction with daratumumab (see table C)

 

Table B - Bortezomib Dosage with Neurotoxicity:

Severity of Neurotoxicity

Bortezomib Dose

Grade 1 (paresthesias, 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)

Reduce dose to 1 mg/m2

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.

Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life-threatening or leads to paralysis, and/or severe autonomic neuropathy)

Discontinue permanently


Table C - Daratumumab Infusion-related reactions:

IRR Severity

Infusion Rate Modification

Grade 1 to 2

(mild to moderate)

Interrupt infusion; treat symptoms.

When resolved, resume infusion at ≤ 50% of the rate at which the reaction occurred.

If no further IRRs, resume rate escalation as appropriate (see Administration section)

Grade 3 (severe)

Interrupt infusion; treat symptoms.

If symptoms resolve and patient stable: consider restarting at ≤ 50% of the rate at which the reaction occurred.

If no further IRRs, resume rate escalation as appropriate (see Administration section)

If grade 3 reaction recurs, repeat above procedure.

if ≥ grade 3 IRRs at subsequent infusions: discontinue

Anaphylaxis or

Grade 4

(life threatening)

Discontinue permanently; manage adverse event appropriately

 



Hepatic Impairment

Hepatic Impairment

Daratumumab Dose

Mild (total bilirubin 1 to 1.5 times ULN or AST > ULN) No dose adjustment necessary
Moderate (total bilirubin 1.5 to 3 times ULN and any AST) No data
Severe impairment (total bilirubin >3 times ULN and any AST)

 

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 times ULN

> ULN

No change

> 1 – 1.5 times ULN

Any

No change

> 1.5 – 3 times 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.

> 3 times ULN

Any


Renal Impairment

Dose adjustments for bortezomib and daratumumab are not necessary in patients with renal insufficiency.

Formal studies have not been conducted with daratumumab; the drug is not renally cleared.

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 adjustments necessary.  No overall differences in safety or effectiveness were observed.


 
F - Adverse Effects

Refer to bortezomib, daratumumab, dexamethasone 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
  • Infection (includes atypical, viral reactivation; may be severe)

 

 

  • Infusion-related reaction with daratumumab (includes CRS / anaphylaxis; may be severe) 
  • Myelosuppression +/- bleeding (may be severe)
  • Neuropathy (may be severe) 
  • Constipation (may be severe) 
  • Musculoskeletal pain
  • Cough, dyspnea 
  • Rash (may be severe)
  • Insomnia
  • Edema
  • Abdominal pain
  • Nasal congestion, rhinitis
  • Abnormal electrolytes
  • Hypertension (may be severe)
  • Hypotension (may be severe)
  • Headache
  • Dizziness 
  • Anorexia
  • Corticosteroid effects (GI irritation, mood changes, hyperglycemia, insomnia)

 

  • Arrhythmia, QT prolongation 
  • Pulmonary hypertension
  • Nephrotoxicity
  • Hyperuricemia
  • Hepatotoxicity
  • Hypersensitivity
  • Pneumonitis
  • Pancreatitis
  • PRES / PML
  • GI obstruction / perforation
  • Secondary malignancy
  • Tumour lysis syndrome
  • DIC
  • Hemolytic uremic syndrome
  • Sudden death
  • Optic neuritis
  • Seizure
  • Graft loss
  • Corticosteroid effects (osteoporosis, cataracts)
 
G - Interactions

Refer to bortezomib, daratumumab, dexamethasone drug monograph(s) for additional details


  • Daratumumab interferes with indirect antiglobulin (Coombs) test by binding to CD38 on RBCs. Daratumumab-mediated positive Coombs test may persist for up to 6 months after treatment completion. Blood should be typed and screened prior to initiating treatment. Notify blood transfusion centres of this in the event of a planned transfusion and educate patients.

  • Daratumumab may interfere with the serum protein electrophoreses (SPE) and immunofixation (IFE) assays used to monitor M-protein. This can impact the monitoring of response and disease progression in some patients with IgG kappa myeloma protein.

  • Use bortezomib with caution with strong CYP3A4 inhibitors; monitor for toxicity

  • Avoid strong CYP3A4 inducers if possible; monitor for reduced bortezomib efficacy

  • Monitor with other drugs associated with peripheral neuropathy

  • Avoid use of green tea and vitamin C during bortezomib treatment

 
H - Drug Administration and Special Precautions

Refer to bortezomib, daratumumab, dexamethasone drug monograph(s) for additional details


Administration

Bortezomib

  • 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 to protect from light.


Daratumumab

  • Daratumumab infusion should be administered at the appropriate initial infusion rate with incremental escalation. Subsequent infusion rate escalation or dilution reduction should only be considered if the previous infusion was well-tolerated (Table D).

    Table D: Standard infusion rates
     
      Dilution volume Initial Infusion Rate (1st hr) Increments of infusion rate Max infusion rate Approximate infusion time
    Week 1 (single dose infusion) 1000 mL 50 mL/hr 50 mL/hr every hour 200 mL/hr 6.5 hr
    Week 1 (split dose infusion; applicable to days 1 and 2) 500 mL 50 mL/hr 50 mL/hr every hour 200 mL/hr 4 hr
    Week 2a 500 mL 50 mL/hr 50 mL/hr every hour 200 mL/hr 4 hr
    Subsequent Infusionsb 500 mL 100 mL/hr 50 mL/hr every hour 200 mL/hr 3.25 hr

    a If single dose infusion is used for week 1, the 500 mL dilution volume for the 16 mg/kg dose should be used only if there were no IRRs in the previous week.

    b Initial infusion rate should only be modified if treatment in Weeks 1 and 2 were well-tolerated (no ≥ grade 1 IRRs during ≥100 mL/hr).
     

  • Missed doses should be administered as soon as possible and the dosing schedule adjusted accordingly. The treatment interval should be maintained.

  • Daratumumab should be diluted in 0.9% Sodium Chloride; remove a volume from the IV bag that is equal to the required volume of daratumumab solution.

  • Daratumumab solution is colourless to yellow.

  • The diluted solution may develop very small, translucent to white proteinaceous particles. Do not use if opaque particles, discolouration, or other foreign particles.

  • Administer by IV infusion using an infusion set with a flow regulator and an in-line, low protein-binding filter (0.22 or 0.2 µm). Polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE administration sets must be used.

  • Do not infuse concomitantly in the same IV line with other agents.

  • Store vials at 2oC - 8oC

  • Do not shake or freeze, protect from light.
     

Dexamethasone:

  • Oral tablets for self-administration

  • Given with food, preferably in the morning

  • Store tablets at room temperature


Contraindications

  • Patients with hypersensitivity to bortezomib, boron, mannitol, daratumumab or any ingredients in the formulations or components of the containers

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

 

Warnings/Precautions

  • Daratumumab can cause severe infusion-related reactions (IRRs), including anaphylaxis. It should only be administered by healthcare professionals with appropriate medical support to manage these reactions. Pre and post infusion medications should be administered (see Premedication and Supportive Measures section).

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

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

  • Use bortezomib 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:

  • Daratumumab and bortezomib should not be used during pregnancy. If exposure to daratumumab occurred in utero, live vaccines should not be administered to the infant until a hematology evaluation has been completed. Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.

  • Breastfeeding is not recommended.

  • Fertility Effects:

    • Daratumumab: No data

    • Bortezomib: 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; Type and screen prior to starting daratumumab. In the event of a planned transfusion, notify blood transfusion centres.

  • CBC with differential; baseline and before each dose

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

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

  • HBV serology; Baseline for all patients and as clinically indicated. For patients with evidence of HBV serology at baseline, monitor during treatment and for at least 6 months post treatment. Consult with an expert in HBV.

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

  • Clinical toxicity assessment for infusion-related reactions, infection, anemia, bleeding, fatigue, hypotension, neurotoxicity, respiratory problems, musculoskeletal pain, tumour lysis syndrome, skin changes, neurologic, GI and cardiovascular 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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K - References

Bortezomib and daratumumab drug monographs, Cancer Care Ontario.

Gut N, Yucebay F, Dempsey J, et al.  Efficacy of once-weekly bortezomib with daratumumab for patients with relapsed or refractory multiple myeloma.  Blood 2018;132:1958.

Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016;375:754-66.

Palumbo A, Chanan-Khan A, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study. J Clin Oncol 2016;34, suppl;abstr LBA4.


July 2019 Added Hepatitis B Virus Reactivation warning and alternative bortezomib and dexamethasone dosing and schedule. Updated Administration Guidelines section.


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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.
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