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DARA(MNT)

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

DARA(MNT) Regimen
Daratumumab Maintenance


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

As maintenance treatment after 8 cycles of BORTDEXADARA in patients with multiple myeloma who have received at least one prior therapy.


Supplementary Public Funding

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

 
B - Drug Regimen

As maintenance treatment after 8 cycles of BORTDEXADARA:

 

daratumumab
16 mg /kg IV Days 1

 

 

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C - Cycle Frequency

REPEAT EVERY 28 DAYS

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Consider antiviral prophylaxis for herpes zoster reactivation.

 

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

  • corticosteroid IV (methylprednisolone 100 mg IV, or equivalent)*

  • 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#

*The dose of corticosteroid may be reduced (e.g. methylprednisolone 60 mg IV or equivalent) following the 2nd infusion

#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 for daratumumab monotherapy:

  • corticosteroid oral (20 mg methylprednisolone PO, or equivalent) for 2 days post-infusion

  • In patient with a history of chronic obstructive pulmonary disorder, consider bronchodilators (short and long acting), and inhaled corticosteroids **

**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

No dose reductions of daratumumab are recommended. A dose delay may be required in case of myelosuppression. Consider supportive care with transfusions or growth factors, as needed.

Hepatitis B virus (HBV) reactivation: Hold daratumumab, concomitant steroids and chemotherapy. Consult with a HBV expert and manage appropriately. Restart of daratumumab treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.


Table 1:  Infusion Rate Modifications for 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 Table 2)

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 Table 2)

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)

 

 


Renal Impairment

No dose adjustment is necessary.  Formal studies have not been conducted; daratumumab is not renally cleared.


Dosage in the Elderly

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

 


 
F - Adverse Effects

Refer to daratumumab 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

  • Infection (Includes atypical, viral reactivaton; may be severe)
  • Infusion related reaction (includes CRS / anaphylaxis;  may be severe)
  • Fatigue
  • Myelosuppression (may be severe)
  • Nausea, vomiting
  • Musculoskeletal pain

 

  • Cough, dyspnea
  • Nasal congestion, rhinitis
  • Diarrhea
  • Anorexia, weight changes
  • Constipation
  • Abnormal electrolytes
  • Headache
  • Hypertension (may be severe)
  • Nephrotoxicity
  • Hepatotoxicity
  • Hyperuricemia
  • Secondary Malignancy (Basal cell carcinoma)
  • Hypotension

 

 

 

 
G - Interactions

Refer to daratumumab drug monograph(s) for additional details


  • No formal drug interaction studies have been conducted.  IgG1 molecules are biotransformed by degradation into small peptides and amino acids via catabolic pathways.
     
  • Daratumumab interferes with the 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. Patient's 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.
 
H - Drug Administration and Special Precautions

Refer to daratumumab drug monograph(s) for additional details


Administration

  • 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 2).

    Table 2: 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.



Contraindications

  • Patients with a history of severe hypersensitivity to daratumumab or who have hypersensitivity to any ingredient in the formulation or component of the container.
     

Other 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).

 

Pregnancy and Lactation:

  • Daratumumab should not be used during pregnancy unless the benefit of treatment outweighs potential risks to the fetus. If exposure to daratumumab ocurred 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.

  • Human IgG is excreted in breast milk. Breastfeeding is not recommended.

  • Fertility: No data.

     

     

 
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

  • CBC; Baseline and before each dose

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

  • Electrolytes, renal function tests; Baseline and as clinically indicated
  • Liver function tests; 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

  • Clinical toxicity assessment for infusion-related reactions, hypersensitivity, infection, anemia, bleeding, respiratory problems, musculoskeletal pain, skin changes, GI and cardiac effects; Baseline and at each visit

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


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J - Administrative Information

Approximate Patient Visit
3.5 hours
Pharmacy Workload (average time per visit)
37.85 minutes
Nursing Workload (average time per visit)
74.833 minutes
 
K - References

July 2019 Updated emetic risk category and Administration Guidelines section. Added Hepatitis B Virus Reactivation warning.


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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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