Daratumumab is an IgG1Ƙ human monoclonal antibody (mAb) that targets CD38 on the surface of cells in a variety of hematological malignancies. Based on in vitro studies, by binding to CD38, daratumumab induces immune mediated tumour cell death or apoptosis through Fc mediated cross-linking.
Time to steady state: approx. 5 months into the monthly dosing period (by 21st infusion)
Likely via degradation into small peptides and amino acids via catabolic pathways.
Rate decreases with increasing doses across the dose levels and with repeated dosing
Terminal half-life increases with increasing dose and with repeated dosing
Mean estimated terminal half-life following the 1st 16mg/kg dose: 9 Days
Upon complete saturation of target mediated clearance and repeat dosing: 18 days
In combination with bortezomib, melphalan and prednisone, for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.
For the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD.*
*Approval was based on the primary efficacy endpoint of overall response rate demonstrated in a single-arm study.
Extravasation Potential: None
Adverse effects described below were reported in ≥ 2% of patients from three pooled open label clinical studies that included patients with relapsed and refractory multiple myeloma treated with 16mg/kg daratumumab monotherapy. Severe adverse events from other studies or post-marketing may also be included.
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Hypertension (10%) (may be severe)||I E|
|Hypotension (5%)||I E|
|Palpitations (3%)||I E|
|Dermatological||Rash, pruritus (3%)||E|
|Gastrointestinal||Abdominal pain (6%)||E|
|Anorexia, weight changes (15%)||E|
|Nausea, vomiting (28%)||I E|
|General||Edema - limbs (7%)||E|
|Hematological||Myelosuppression ± infection, bleeding (28%)||E D|
|Hepatobiliary||↑ LFTs (4%)||E D|
|Hypersensitivity||Infusion related reaction (39%) (for first infusion) (including CRS and anaphylaxis - 6% severe)||I E|
|Immune||Other - Antibody formation (<1%; in combination therapy)||D|
|Infection||Infection (59%) (including atypical and viral reactivation - 10% severe)||E|
|Metabolic / Endocrine||Abnormal electrolyte(s) (12%)||E|
|Musculoskeletal||Musculoskeletal pain (26%)||E|
|Neoplastic||Secondary malignancy (3%) (Basal cell carcinoma)||D L|
|Nervous System||Anxiety (6%)||E|
|Neuropathy (5%)||E D|
|Ophthalmic||Blurred vision (6%)||E|
|Renal||Renal failure (<2%)||E D|
|Respiratory||Cough, dyspnea (24%)||E|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for daratumumab include infection, fatigue, infusion related reaction, myelosuppression ± infection, bleeding, nausea, vomiting, musculoskeletal pain, cough, dyspnea, fever, rhinitis and diarrhea.
The majority of infusion reactions (IRs) (96%) occurred during the first infusion with incidence declining to 4% with subsequent infusions. Most reactions were grade 1 or 2, however, IRRs can be severe and include respiratory symptoms, cytokine release syndrome (CRS), anaphylaxis, nausea, rash and hypotension. Most reactions occurred during infusion or within 4 hours of completion (median onset was 1.5 h). Without post-infusion medications, infusion reactions can occur up to 48 hours post infusion.
Infections may be severe, including when administered in combination. Opportunistic infections and herpes zoster virus reactivation, some with a fatal outcome were also reported.
Daratumumab may worsen myelosuppression when used in combination with other chemotherapy agents for the treatment of multiple myeloma.
HBV screening should be performed in all patients prior to starting daratumumab.
Consider antiviral prophylaxis for herpes zoster reactivation.
Patient's blood should be typed and screened prior to starting daratumumab given the potential for interference with the indirect Coombs test.
Pre-medications (prophylaxis for infusion reaction) for daratumumab monotherapy∆:
To be given at least 1 hour prior to infusion:
- Corticosteroid IV (e.g. methylprednisolone 100 mg or equivalent)*†
- 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**
*This dose may be reduced following the second infusion (i.e. IV methylprednisolone 60 mg or equivalent).
†For daratumumab combination therapy, corticosteroid IV/PO (e.g. dexamethasone 20 mg) is recommended.
**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 for daratumumab monotherapy:
- Oral corticosteroid (e.g. methylprednisolone 20 mg or equivalent) for 2 days post-infusion‡
- Consider bronchodilators (e.g. short and long acting) and inhaled corticosteroids if chronic obstructive pulmonary disorder&***
‡For daratumumab combination therapy, corticosteroid PO (e.g. dexamethasone 20 mg) on the day after infusion is recommended.
&For daratumumab combination therapy, 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.
For daratumumab pre/post-infusion medication in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone, see the respective regimen monographs.
Daratumumab 16mg/kg* IV (monotherapy):
|Weeks 1 to 8||Weekly|
|Weeks 9 to 24||Every 2 weeks|
|Week 25 onwards until disease progression||Every 4 weeks|
*Splitting the first dose over 2 days has been described (8 mg/kg days 1 and 2) and may be considered. The same premedications listed above should be administered prior to both treatment days (Reece et al 2018).
For daratumumab dosing in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone, see the respective regimen monographs.
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: Management of Infusion Reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
|1 or 2||
|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)|
No dose adjustment is necessary. Formal studies have not been conducted; daratumumab is not renally cleared.
No dose adjustments necessary. No overall differences in safety or effectiveness were observed.
Based on population PK analysis, there are no significant differences between genders.
No significant differences were seen between white and non-white patients in the population PK analysis.
Safety and efficacy have not been established.
- 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, 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).
c 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.
- Patients with a history of severe hypersensitivity to daratumumab or who have hypersensitivity to any ingredient in the formulation or component of the container.
- 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 Dosing section).
Other Drug Properties:
Crosses placental barrier:
Has not been studied in pregnant women. IgG1 monoclonal antibodies are known to transfer across the placenta.
Based on its mechanism of action, it may cause fetal myeloid or lymphoid-cell depletion and decreased bone density. Daratumumab should not be used during pregnancy unless the benefit of treatment outweighs potential risks to the fetus. 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.
Human IgG is excreted in breast milk.
No information available
- 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.
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
|Baseline and before each dose|
|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|
|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
New Drug Funding Program (NDFP Website )
- Daratumumab – In Combination with Lenalidomide and Dexamethasone for Relapsed Multiple Myeloma
- Daratumumab – In Combination with Bortezomib and Dexamethasone for Relapsed Multiple Myeloma
Product Monograph. Darzalex (daratumumab). Janssen Inc. May 2019.
Lonial A, Weiss BW, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Jan; 387: 1551-60.
Nooka AK, Gleason C, Sargeant MO, et al. Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab. J Oncol Pract. 2018 Jul;14(7):414-422
Reece DE, Phillips MJ. Infusion Reactions with Monoclonal Antibody Therapy in Myeloma: Learning from Experience. J Oncol Pract. 2018 Jul;14(7):425-426
September 2019 Updated infusion reaction information in Dosing and Administration sections
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