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DARADEXALENA

Cancer Type: Hematologic, Multiple Myeloma  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Daratumumab – In Combination with Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma
ODB - General Benefit
    dexamethasone
Exceptional Access Program
    lenalidomide - In combination with daratumumab and dexamethasone for the treatment of relapsed multiple myeloma, with specific criteria
A - Regimen Name

DARADEXALENA Regimen
daratumumab-dexamethasone-lenalidomide


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

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

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

lenalidomide
Exceptional Access Program (lenalidomide - In combination with daratumumab and dexamethasone for the treatment of relapsed multiple myeloma, with specific criteria)

 
B - Drug Regimen

Cycles 1 to 2:

daratumumab

1

16* mg /kg IV Days 1, 8, 15, 22
dexamethasone
40** mg PO Days 1, 8, 15, 22
lenalidomide
25 mg PO Days 1 to 21

 

Q28 Days

 

Cycles 3 to 6:

daratumumab

1

16 mg /kg IV Days 1 and 15
dexamethasone
40** mg PO Days 1, 8, 15 and 22
lenalidomide
25 mg PO Days 1 to 21

 

Q28 Days

 

Cycle 7 and beyond:

daratumumab

1

16 mg /kg IV Day 1
dexamethasone
40** mg PO Days 1, 8, 15 and 22
lenalidomide
25 mg PO Days 1 to 21

 

Lenalidomide may only be prescribed and dispensed by physicians and pharmacists registered with RevAid®. Patients must also be registered and meet all conditions of the RevAid® program. Call 1-888-RevAid1 or log onto www.RevAid.ca

1. 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 premedications 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 20mg pre-medication, on the days of daratumumab infusion, and 20mg post-medication, the days after the infusion.

 

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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

  • For lenalidomide, patients must also be registered and meet all conditions of the RevAid program, including contraception.

  • Consider prophylaxis for venous thromboembolism. For patients who are not at high risk for bleeding or VTE, either low-dose aspirin 81-100 mg PO daily or enoxaparin 40mg SC daily can be used.     

  • Careful consideration and monitoring must be taken with erythropoietin stimulating agents (ESAs), since the concomitant use of ESAs with lenalidomide may potentiate the risk of thrombosis.

  • RBC or platelet transfusions with lenalidomide dose reductions/interruptions may be appropriate in severe / symptomatic anemia or thrombocytopenia


Pre-medications (prophylaxis for infusion reaction):

To be given at least 1 hour prior to daratumumab infusion:

  • Dexamethasone 20 mg IV/PO*
  • Oral antipyretic (e.g. acetaminophen 650-1000 mg)
  • H1-receptor antagonist IV/PO (e.g. diphenhydramine 25-50 mg 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. Dexamethasone on the day of infusion may be given as part of pre-/post-medications for daratumumab; 20 mg IV/PO on the day of daratumumab infusion and 20 mg PO on the day after infusion. For patients receiving reduced dose dexamethasone 20 mg weekly, the entire 20 mg dose has been given prior to the daratumumab infusion in some clinical trials.

**The addition of montelukast given prior to the first infusion numerically reduced the incidence of respiratory IRs in the study by Nooka et al.

 

Post-infusion medications (prevention of delayed reactions):

  • Dexamethasone 20 mg PO on the day after daratumumab infusion* 
  • Consider bronchodilators (e.g. short and long acting) and inhaled corticosteroids if chronic obstructive pulmonary disorder&****

*Dexamethasone on the day of infusion may be given as part of pre-/post-medications for daratumumab; 20 mg IV/PO on the day of daratumumab infusion and 20 mg PO on the day after infusion. For patients receiving reduced dose dexamethasone 20 mg weekly, the entire 20 mg dose has been given prior to the daratumumab infusion in some clinical trials.

&Consider adding an H1-receptor antagonist if the patient is at higher risk of respiratory complications.

***These may be discontinued after the 4th infusion if no major IRs occurred.

 

 
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. 

Women of child bearing potential must have two negative pregnancy tests before initiating treatment. Assess risk of second primary malignancies prior to starting treatment. Refer to www.revaid.ca

Optimal control of thyroid function is recommended prior to starting lenalidomide treatment

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 lenalidomide, dose reductions were permitted at the following dose levels:

Dose level Lenalidomide dose (mg)
0 25
-1 15
-2 10
-3 5
-4 Discontinue

 

Suggested dose modifications:

Toxicity Daratumumab Lenalidomide (counts x 109/L)
Thrombocytopenia Hold* for grade 3 or higher thrombocytopenia with bleeding

Hold when platelet count first falls to < 30, monitor CBC weekly

When count returns to ≥ 30, resume at one dose level reduction.

Neutropenia Hold* for grade 4 hematologic toxicity

Hold when ANC first falls to < 1, start G-CSF support, monitor CBC weekly.

When count returns to  ≥ 1 and neutropenia is only observed  toxicity, resume at the previous dose.

When count returns to  ≥ 1 and other toxicity is observed, resume at one dose level reduction.

Grade 3 or higher non-hematologic toxicities** Hold*

If related to lenalidomide, hold until ≤ grade 2. 

Resume at one dose level reduction. 

Grade 2 or higher exfoliative rash, SJS, TENS or pneumonitis n/a

Discontinue if skin toxicity.

For suspected pneumonitis, hold and investigate. Discontinue if confirmed.

Increased LFTs n/a Hold and consider restarting at a lower dose when ≤ baseline.
HBV reactivation

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.

*Resume when toxicity has resolved to ≤ grade 2

**except for grade 3 nausea/vomiting responsive to antiemetics, grade 3 diarrhea responsive to antidiarrheals, isolated grade 3 GGT elevation or grade 3 fatigue for < 7 days post-infusion

 

 Management of Daratumumab Infusion-related Reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Grade
Management
Re-challenge
1 or 2
  • Stop or slow the infusion rate.
  • Manage the symptoms.
     

Restart:

  • Once symptoms have resolved, the infusion may be restarted at a rate of no more than 50% of the rate at which the reaction occurred.
  • If no reaction occurs, escalate the rate at no more than 50 mL/hour every hour.
  • Re-challenge with pre-medications and with infusion rate modification (eg. Table D in Drug Administration and Special Precautions section).
3
  • Stop treatment.
  • Aggressively manage symptoms.
     

Restart:

  • Once symptoms have resolved, the infusion may be restarted at a rate of no more than 50% of the rate at which the reaction occurred.
  • If no reaction occurs, escalate the rate at no more than 50 mL/hour every hour.
  • Re-challenge with pre-medications and with infusion rate modification (eg. Table D in Drug Administration and Special Precautions section).
  • If a grade 3 IR recurs for the 3rd time, discontinue permanently (do not re-challenge).
4
  • Stop treatment.
  • Aggressively manage symptoms.
  • Discontinue permanently (do not re-challenge).



Hepatic Impairment

 For dexamethasone, no dosage adjustment is required.

Hepatic Impairment Lenalidomide dose

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

For dexamethasone, no dosage adjustment is necessary. 

Daratumumab is not renally cleared. For lenalidomide, clearance is decreased in renal impairment. The following dosage adjustments are suggested:

CrCl (mL/min) Lenalidomide starting dose* Daratumumab Dose
30-60 10 mg daily No dose adjustment necessary
< 30 not requiring dialysis 15 mg every other day
< 30 requiring dialysis 5 mg daily (after dialysis on dialysis days)

*maintain day 1-21, q28 day schedule


Dosage in the Elderly

For daratumumab, no overall differences in safety or efficacy were observed.

For lenalidomide, the incidences of adverse events were significantly higher in patients over 65, including constipation, confusion, dyspnea, atrial fibrillation, diarrhea, fatigue, pulmonary embolism and syncope. This may be related to renal impairment. Monitor elderly patients closely and adjust the dose for renal impairment as suggested under "dosage with renal impairment".

Patients older than 75 or those with a BMI < 18.5 received dexamethasone at a reduced dose of 20 mg weekly in some clinical trials.


 
F - Adverse Effects

Refer to daratumumab, dexamethasone, lenalidomide, 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 reactivation; may be severe)
  • Infusion related reaction (daratumumab; includes CRS / anaphylaxis, may be severe)
  • Fatigue
  • Constipation
  • Diarrhea
  • Myelosuppression +/- bleeding (may be severe)
  • Musculoskeletal pain
  • Edema
  • Headache
  • Nausea, vomiting
  • Cough, dyspnea

 

  • Fever
  • Dizziness
  • Rash (may be severe)
  • Tremor
  • Anorexia
  • Blurred vision
  • Dyspepsia
  • Nasal congestion, Rhinitis
  • Abnormal electrolytes
  • Dysgeusia
  • Depression
  • Abdominal pain
  • Hypertension (may be severe)
  • Corticosteroid effects (GI irritation, mood changes, hyperglycemia, insomnia)
  • Arterial / venous thromboembolism
  • Arrhythmia
  • Cardiotoxicity
  • Hypotension
  • Nephrotoxicity
  • Hepatotoxicity
  • Hyperuricemia
  • Secondary malignancy
  • Adrenal insufficiency
  • Hypersensitivity
  • Pancreatitis
  • Cholecystitis
  • Rhabdomyolysis
  • Hemolysis
  • Tumour lysis syndrome
  • Pneumonitis
  • Corticosteroid effects (osteoporosis, cataracts)
 
G - Interactions

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


  • Lenalidomide increases the concentration of digoxin. Use caution and monitor digoxin levels.

  • Lenalidomide increases the risk of thromboembolism, and can have an additive effect with hormonal therapy, erythropoietic agents, and corticosteroids.

  • 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.

 
H - Drug Administration and Special Precautions

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


Administration

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,c 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).

    If the patient did not experience an IR in the first 2 infusions of daratumumab, consideration can be given to administer daratumumab as a rapid infusion starting with the 3rd dose (20% of the dose over 30 minutes at 200 mL/hour, then the remaining 80% of the dose over 60 minutes at 450 mL/hour).

     

  • 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.

​​​​​Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Lenalidomide

  • Oral self-administration; swallow capsules whole; they should not be broken, chewed, or opened. Do not extensively handle the capsules.

  • Give capsules preferably with water, either with or without food. Do not remove from blister packs until ready to take the dose. 

  • Note:  Females who could become pregnant, or who plan to become pregnant can handle lenalidomide capsules if they are using latex gloves.

  • If a dose is missed, it may be taken up to 12 hours after the time it is normally taken.  Otherwise, skip this and take the next dose on the following day at its usual scheduled time.

  • Store capsules at room temperature (15 to 30°C)

  • Drug available by outpatient prescription in pharmacy registered with the RevAid® program. Please call 1-888-RevAid-1 or log onto www.RevAid.ca

 

Dexamethasone

  • Oral tablets for self-administration

  • Given with food, preferably in the morning

  • Store tablets at room temperature

 

Contraindications

  • Patients with a history of severe hypersensitivity to daratumumab or who have hypersensitivity to lenalidomide, pomalidomide, thalidomide or dexamethasone or who have hypersensitivity to any ingredients in the formulations or components of the containers.

  • Pregnant and breastfeeding women.

  • Women at risk of being pregnant and male patients who do not comply with contraception requirements.

 

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).

  • Lenalidomide contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption

  • Use with caution and consider venous thromboembolism prophylaxis when used in combination with corticosteroids or thrombogenic agents, such as hormones and erythropoietin (see adverse effects section)

  • Exercise caution in patients with risk factors for arterial thromboembolism (e.g. hypertension and hyperlipidemia), or risk factors for atrial fibrillation (e.g. electrolyte abnormalities, pre-existing heart disease, hypertension, infection).

  • Use with caution in patients with high tumour burden; monitor closely and use appropriate precautions for tumour lysis syndrome.

  • Use with caution and monitor closely in patients with previous viral infections such as HBV and herpes zoster.

 

Pregnancy and Lactation

  • This regimen is contraindicated in pregnancy and in females and males of childbearing potential who do not comply with the contraception conditions of the RevAid® program (see the lenalidomide drug monograph for details).

  • Breastfeeding is contraindicated.

  • Fertility Effects:

    • Daratumumab: No data

    • Lenalidomide: Unlikely

 
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 of daratumumab; if daratumumab is held, before each cycle of lenalidomide and as clinically indicated

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

  • Liver function tests; Baseline and at each visit

  • Renal function tests and electrolytes; Baseline and at each visit

  • Thyroid function tests; Baseline and as clinically indicated

  • RevAid requirements regarding pregnancy tests for women of child-bearing potential; Before starting and as indicated per RevAid

  • 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

  • Cancer screening for occurrance of second primary malignancy; Assess risk prior to starting treatment; then at each visit or as clinically indicated

  • Clinical toxicity assessments and grading of infusion-related reactions with daratumumab, cardiac and respiratory symptoms, rash, diarrhea, fatigue, constipation, infection (including viral reactivation), bleeding, tumour lysis syndrome, thromboembolism; At each visit

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

Suggested Clinical Monitoring

  • ECG; Baseline; repeat if arrhythmia suspected

  • INR in patients receiving warfarin; Baseline and as clinically indicated


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J - Administrative Information

dexamethasone and lenalidomide: outpatient prescriptions for home administration

daratumumab infusion:


Approximate Patient Visit
1st infusion: 7 hours; 2nd infusion: 4 hours; subsequent infusions: 3.5 hours
Pharmacy Workload (average time per visit)
37.85 minutes
Nursing Workload (average time per visit)
74.83 minutes
 
K - References

Daratumumab and lenalidomide drug monographs, Cancer Care Ontario.

Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators.. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331.
 


September 2020 Updated infusion reaction information in Premedication and Supportive Measures, Dose Modifications and Drug Administration and Special Precautions sections


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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.
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.