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Dosage & administration

DOSAGE AND ADMINISTRATION

  • Pre-medicate with corticosteroids, antipyretics and antihistamines. (2.3 )
  • Dilute and administer as an intravenous infusion. (2.5 )
  • Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule. (2.2 )
  • Administer post-infusion medications. (2.3 )

Important Dosing Information

Recommended Dosage

Infusion Rates

Administer DARZALEX intravenously at the infusion rate described below in Table 6. Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions.

The recommended dose of 16 mg/kg to be administered on Day 1 when DARZALEX is administered as monotherapy or in combination may be split over two consecutive days, such that an 8 mg/kg dose is administered on Day 1 and Day 2, respectively.

Table 6: Infusion Rates for DARZALEX (16 mg/kg) Administration
Dilution volume Initial rate (first hour) Rate increment Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions. Maximum rate
Week 1 Infusion
Option 1 (Single dose infusion)
Week 1 Day 1 (16 mg/kg) 1,000 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Option 2 (Split dose infusion)
Week 1 Day 1 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Week 1 Day 2 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Week 2 (16 mg/kg) Use a dilution volume of 500 mL for the 16 mg/kg dose only if there were no infusion-related reactions the previous week. Otherwise, use a dilution volume of 1,000 mL. 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Week 3 onwards (16 mg/kg) Use a modified initial rate (100 mL/hour) for subsequent infusions (i.e. Week 3 onwards) only if there were no infusion-related reactions during the previous infusion. Otherwise, continue to use instructions indicated in the table for the Week 2 infusion rate. 500 mL 100 mL/hour 50 mL/hour every hour 200 mL/hour

Missed DARZALEX Doses

If a dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.

Recommended Concomitant Medications

Post-infusion Medication

Administer the following post-infusion medications:

  • Monotherapy:
    Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX.
    In Combination:
    Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of a DARZALEX infusion.
    If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed [see Clinical Studies (14) ].

For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major infusion-related reaction.

Prophylaxis for Herpes Zoster Reactivation

Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following the end of treatment [see Adverse Reactions (6.1) ].

Dosage Modifications for Adverse Reactions

No dose reductions of DARZALEX are recommended. Consider withholding DARZALEX to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.3 , 5.4) ] .

For information concerning drugs given in combination with DARZALEX, see manufacturer's prescribing information.

Infusion-Related Reactions

For infusion-related reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion-related reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below [see Warnings and Precautions (5.1) ] .

  • Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6).
  • Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion-related reaction.
  • Grade 4 (life-threatening): Permanently discontinue DARZALEX.

Preparation and Administration

Preparation

DARZALEX is for single dose only.

Prepare the solution for infusion using aseptic technique as follows:

  • Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.
  • DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag [see Description (11) , How Supplied/Storage and Handling (16) ] .
  • Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
  • Remove a volume of 0.9% Sodium Chloride Injection from the infusion bag/container that is equal to the required volume of DARZALEX solution.
  • Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection as specified in Table 6 [see Dosage and Administration (2.2) ] . Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
  • Gently invert the bag/container to mix the solution. Do not shake.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
  • If not used immediately, store the diluted solution refrigerated for up to 24 hours at 2°C to 8°C (36°F to 46°F) and/or at room temperature up to 15 hours at 15°C to 25°C (59°F to 77°F). The room temperature storage includes infusion time. Protect from light during storage. Do not freeze.

Administration

  • If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 micrometer or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.
  • Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.
  • Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
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Darzalex prescribing information

Indications & Usage

INDICATIONS AND USAGE

DARZALEX is indicated for the treatment of adult patients with multiple myeloma:

  • in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy.
  • in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.
  • in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant.
  • in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy.
  • in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.
  • in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
  • as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.
Dosage & Administration

DOSAGE AND ADMINISTRATION

  • Pre-medicate with corticosteroids, antipyretics and antihistamines. (2.3 )
  • Dilute and administer as an intravenous infusion. (2.5 )
  • Recommended dose is 16 mg/kg actual body weight. See full prescribing information for drugs used in combination and schedule. (2.2 )
  • Administer post-infusion medications. (2.3 )

Important Dosing Information

Recommended Dosage

Infusion Rates

Administer DARZALEX intravenously at the infusion rate described below in Table 6. Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions.

The recommended dose of 16 mg/kg to be administered on Day 1 when DARZALEX is administered as monotherapy or in combination may be split over two consecutive days, such that an 8 mg/kg dose is administered on Day 1 and Day 2, respectively.

Table 6: Infusion Rates for DARZALEX (16 mg/kg) Administration
Dilution volume Initial rate (first hour) Rate increment Consider incremental escalation of the infusion rate only in the absence of infusion-related reactions. Maximum rate
Week 1 Infusion
Option 1 (Single dose infusion)
Week 1 Day 1 (16 mg/kg) 1,000 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Option 2 (Split dose infusion)
Week 1 Day 1 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Week 1 Day 2 (8 mg/kg) 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Week 2 (16 mg/kg) Use a dilution volume of 500 mL for the 16 mg/kg dose only if there were no infusion-related reactions the previous week. Otherwise, use a dilution volume of 1,000 mL. 500 mL 50 mL/hour 50 mL/hour every hour 200 mL/hour
Week 3 onwards (16 mg/kg) Use a modified initial rate (100 mL/hour) for subsequent infusions (i.e. Week 3 onwards) only if there were no infusion-related reactions during the previous infusion. Otherwise, continue to use instructions indicated in the table for the Week 2 infusion rate. 500 mL 100 mL/hour 50 mL/hour every hour 200 mL/hour

Missed DARZALEX Doses

If a dose of DARZALEX is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.

Recommended Concomitant Medications

Post-infusion Medication

Administer the following post-infusion medications:

  • Monotherapy:
    Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX.
    In Combination:
    Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after the administration of a DARZALEX infusion.
    If a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX infusion, additional corticosteroids may not be needed [see Clinical Studies (14) ].

For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 DARZALEX infusions, consider discontinuing these additional post-infusion medications, if the patient does not experience a major infusion-related reaction.

Prophylaxis for Herpes Zoster Reactivation

Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX and continue for 3 months following the end of treatment [see Adverse Reactions (6.1) ].

Dosage Modifications for Adverse Reactions

No dose reductions of DARZALEX are recommended. Consider withholding DARZALEX to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.3 , 5.4) ] .

For information concerning drugs given in combination with DARZALEX, see manufacturer's prescribing information.

Infusion-Related Reactions

For infusion-related reactions of any grade/severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion-related reactions may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below [see Warnings and Precautions (5.1) ] .

  • Grade 1–2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 200 mL/hour (Table 6).
  • Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 6. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX upon the third occurrence of a Grade 3 or greater infusion-related reaction.
  • Grade 4 (life-threatening): Permanently discontinue DARZALEX.

Preparation and Administration

Preparation

DARZALEX is for single dose only.

Prepare the solution for infusion using aseptic technique as follows:

  • Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient actual body weight.
  • DARZALEX vials of the same strength with different NDCs are available and can be admixed in the same infusion bag [see Description (11) , How Supplied/Storage and Handling (16) ] .
  • Check that the DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration or other foreign particles are present.
  • Remove a volume of 0.9% Sodium Chloride Injection from the infusion bag/container that is equal to the required volume of DARZALEX solution.
  • Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection as specified in Table 6 [see Dosage and Administration (2.2) ] . Infusion bags/containers must be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
  • Gently invert the bag/container to mix the solution. Do not shake.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or foreign particles are observed.
  • If not used immediately, store the diluted solution refrigerated for up to 24 hours at 2°C to 8°C (36°F to 46°F) and/or at room temperature up to 15 hours at 15°C to 25°C (59°F to 77°F). The room temperature storage includes infusion time. Protect from light during storage. Do not freeze.

Administration

  • If stored in the refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 micrometer or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP or PE.
  • Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.
  • Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
Dosage Forms & Strengths

DOSAGE FORMS AND STRENGTHS

DARZALEX is a colorless to pale yellow, preservative-free solution available as:

Injection:

  • 100 mg/5 mL (20 mg/mL) in a single-dose vial.
  • 400 mg/20 mL (20 mg/mL) in a single-dose vial.
Pregnancy & Lactation

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

DARZALEX can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data ) . There are no available data on the use of DARZALEX in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The combination of DARZALEX and lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Lenalidomide, pomalidomide, and thalidomide are only available through a REMS program. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

Data

Lactation

Risk Summary

There is no data on the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX is administered with lenalidomide, pomalidomide, or thalidomide, advise women not to breastfeed during treatment with DARZALEX. Refer to lenalidomide, pomalidomide, or thalidomide prescribing information for additional information.

Females and Males of Reproductive Potential

DARZALEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] .

Pregnancy Testing

With the combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide, refer to the lenalidomide, pomalidomide, or thalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.

Contraception

Advise females of reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose. Additionally, refer to the lenalidomide, pomalidomide, or thalidomide labeling for additional recommendations for contraception.

Pediatric Use

Safety and effectiveness of DARZALEX in pediatric patients have not been established.

The safety and effectiveness of DARZALEX in combination with chemotherapy were assessed but not established in a single open-label trial (DELPHINUS; NCT03384654) in 34 pediatric patients (2 to <17 years of age) with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. No new safety signals were observed in these pediatric patients. The pharmacokinetic parameters in these pediatric patients were within range of values previously observed in adults with multiple myeloma given the same dose based on body weight.

Geriatric Use

Of the 2,459 patients who received DARZALEX at the recommended dose, 38% were 65 to 74 years of age, and 15% were 75 years of age and older. No overall differences in effectiveness were observed between these patients and younger patients. The incidence of serious adverse reactions was higher in older than in younger patients [see Adverse Reactions (6.1) ] . Among patients with relapsed and refractory multiple myeloma (n=1,213), the serious adverse reactions that occurred more frequently in patients 65 years and older were pneumonia and sepsis. Within the DKd group in CANDOR, fatal adverse reactions occurred in 14% of patients 65 years and older compared to 6% of patients less than 65 years. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the serious adverse reaction that occurred more frequently in patients 75 years and older was pneumonia.

Contraindications

CONTRAINDICATIONS

DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation [see Warnings and Precautions (5.1) ] .

Warnings & Precautions

WARNINGS AND PRECAUTIONS

  • Infusion-related reactions : Interrupt DARZALEX infusion for infusion-related reactions of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening infusion-related reactions and institute appropriate emergency care. (2.4 , 5.1 )
  • Interference with cross-matching and red blood cell antibody screening : Type and screen patients prior to starting treatment. Inform blood banks that a patient has received DARZALEX. (5.2 , 7.1 )
  • Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Dose delay may be required to allow recovery of neutrophils. (5.3 )
  • Thrombocytopenia : Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets. (5.4 )
  • Embryo-Fetal Toxicity : Can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception. (5.6 , 8.1 , 8.3 )

Infusion-Related Reactions

DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported [see Adverse Reactions (6.2) ] .

In clinical trials (monotherapy and combination: N=2,066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). The incidence of infusion modification due to reactions was 36%. Median durations of 16 mg/kg infusions for the Week 1, Week 2, and subsequent infusions were approximately 7, 4, and 3 hours respectively. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion-related reactions occurred up to 48 hours after infusion.

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision [see Adverse Reactions (6.1) ] .

When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption for ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions.

In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 hours for Week 1-Day 1, 4.2 hours for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion [see Dosage and Administration (2.3) ] . Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.4) ] .

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions [see Dosage and Administration (2.3) ] . Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease [see Dosage and Administration (2.3) ] .

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference with Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum [see References (15) ] . The determination of a patient's ABO and Rh blood type are not impacted [see Drug Interactions (7.1) ] .

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX [see Dosage and Administration (2.1) ] .

Neutropenia

DARZALEX may increase neutropenia induced by background therapy [see Adverse Reactions (6.1) ].

Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX until recovery of neutrophils.

Thrombocytopenia

DARZALEX may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1) ].

Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Consider withholding DARZALEX until recovery of platelets.

Interference with Determination of Complete Response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.1) ] . This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

Adverse Reactions

ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.

Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant

Combination Treatment with Lenalidomide and Dexamethasone (DRd)

The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies (14.1) ]. Adverse reactions described in Table 7 reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).

Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).

Table 7: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in MAIA
Body System
Adverse Reaction 		DRd (N=364) Rd (N=365)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
Gastrointestinal disorders
Diarrhea 57 7 0 46 4 0
Constipation 41 1 <1 36 <1 0
Nausea 32 1 0 23 1 0
Vomiting 17 1 0 12 <1 0
Infections
Upper respiratory tract infection Acute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 52 2 <1 36 2 <1
Bronchitis Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis 29 3 0 21 1 0
Pneumonia Atypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis 26 14 1 14 7 1
Urinary tract infection 18 2 0 10 2 0
General disorders and administration site conditions
Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 41 2 <1 0 0 0
Peripheral edema Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling 41 2 0 33 1 0
Fatigue 40 8 0 28 4 0
Asthenia 32 4 0 25 3 <1
Pyrexia 23 2 0 18 2 0
Chills 13 0 0 2 0 0
Musculoskeletal and connective tissue disorders
Back pain 34 3 <1 26 3 <1
Muscle spasms 29 1 0 22 1 0
Respiratory, thoracic and mediastinal disorders
Dyspnea Dyspnea, Dyspnea exertional 32 3 <1 20 1 0
Cough Cough, Productive cough 30 <1 0 18 0 0
Nervous system disorders
Peripheral sensory neuropathy 24 1 0 15 0 0
Headache 19 1 0 11 0 0
Paresthesia 16 0 0 8 0 0
Metabolism and nutrition disorders
Decreased appetite 22 1 0 15 <1 <1
Hyperglycemia 14 6 1 8 3 1
Hypocalcemia 14 1 <1 9 1 1
Vascular disorders
Hypertension Blood pressure increased, Hypertension 13 6 <1 7 4 0

Laboratory abnormalities worsening during treatment from baseline listed in Table 8.

Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA
DRd (N=364) Rd (N=365)
All Grades
(%) 		Grade 3
(%) 		Grade 4
(%) 		All Grades
(%) 		Grade 3
(%) 		Grade 4
(%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
Leukopenia 90 30 5 82 20 4
Neutropenia 91 39 17 77 28 11
Lymphopenia 84 41 11 75 36 6
Thrombocytopenia 67 6 3 58 7 4
Anemia 47 13 0 57 24 0

Combination Treatment with Bortezomib, Melphalan and Prednisone

The safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies (14.1) ]. Adverse reactions described in Table 9 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.

Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).

Table 9: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the D-VMP Arm in ALCYONE
Body System
Adverse Reaction 		D-VMP (N=346) VMP (N=354)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone.
Infections
Upper respiratory tract infection upper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection 48 5 0 28 3 0
Pneumonia pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis 16 12 < 1 6 5 < 1
General disorders and administration site conditions
Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 28 4 1 0 0 0
Peripheral edema edema peripheral, generalized edema, peripheral swelling 21 1 < 1 14 1 0
Respiratory, thoracic and mediastinal disorders
Cough cough, productive cough 16 < 1 0 8 < 1 0
Dyspnea dyspnea, dyspnea exertional 13 2 1 5 1 0
Vascular disorders
Hypertension hypertension, blood pressure increased 10 4 < 1 3 2 0

Laboratory abnormalities worsening during treatment from baseline listed in Table 10.

Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE
D-VMP (N=346) VMP (N=354)
All Grades
(%) 		Grade 3
(%) 		Grade 4
(%) 		All Grades
(%) 		Grade 3
(%) 		Grade 4
(%)
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone.
Thrombocytopenia 88 27 11 88 26 16
Neutropenia 86 34 10 87 32 11
Lymphopenia 85 46 12 83 44 9
Anemia 47 18 0 50 21 0

Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant

Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)

The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies (14.1) ]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.

Serious adverse reactions with a 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%).

Table 11: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DVTd Arm in CASSIOPEIA
Body System
Adverse Reaction 		DVTd (N=536) VTd (N=538)
All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.
Note: Hematology laboratory related toxicities were excluded and reported separately in the table below.
General disorders and administration site conditions
Infusion-related reactions Infusion-related reaction includes terms determined by investigators to be related to infusion 35 3 <1 0 0 0
Pyrexia 26 2 <1 21 2 0
Gastrointestinal disorders
Nausea 30 4 0 24 2 <1
Vomiting 16 2 0 10 2 0
Infections
Upper respiratory tract infection Laryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection 27 1 0 17 1 0
Bronchitis Bronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis 20 1 0 13 1 0
Respiratory, thoracic and mediastinal disorders
Cough Cough, Productive cough 17 0 0 9 0 0
Vascular disorders
Hypertension 10 4 0 5 2 0
Table 12: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA
DVTd (N=536) VTd (N=538)
All Grades
(%) 		Grade 3
(%) 		Grade 4
(%) 		All Grades
(%) 		Grade 3
(%) 		Grade 4
(%)
Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.
Lymphopenia 95 44 15 91 37 10
Leukopenia 82 14 10 57 6 9
Thrombocytopenia 81 9 5 58 8 3
Neutropenia 63 19 14 41 10 9
Anemia 36 4 0 35 5 0

Herpes Zoster Virus Reactivation

Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2–5% of patients receiving DARZALEX.

Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System disorders: Anaphylactic reaction, IRR (including deaths)

Gastrointestinal disorders: Pancreatitis

Infections: Cytomegalovirus, Listeriosis

Drug Interactions

DRUG INTERACTIONS

Effects of Daratumumab on Laboratory Tests

Interference with Indirect Antiglobulin Tests (Indirect Coombs Test)

Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References (15) ] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs.

If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices.

Interference with Serum Protein Electrophoresis and Immunofixation Tests

Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.

Description

DESCRIPTION

Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody that binds to CD38 antigen. It is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.

DARZALEX ® (daratumumab) injection is supplied as a colorless to pale yellow preservative-free solution for intravenous use in a single-dose vial. The pH is 5.5.

Each DARZALEX 20 mL single-dose vial contains (NDC 57894-502-20) 400 mg daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and Water for Injection, USP.

Each DARZALEX 5 mL single-dose vial contains (NDC 57894-502-05) 100 mg daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and Water for Injection, USP.

Each DARZALEX 20 mL single-dose vial contains (NDC 57894-505-20) 400 mg daratumumab, L-histidine (7 mg), L-histidine hydrochloride monohydrate (32.6 mg), L-methionine (20 mg), polysorbate 20 (8 mg), sorbitol (1093 mg), and Water for Injection, USP.

Each DARZALEX 5 mL single-dose vial contains (NDC 57894-505-05) 100 mg daratumumab, L-histidine (1.8 mg), L-histidine hydrochloride monohydrate (8.2 mg), L-methionine (5 mg), polysorbate 20 (2 mg), sorbitol (273.3 mg), and Water for Injection, USP.

Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T regs ) and B cells (CD38+B regs ) are decreased by daratumumab.

Pharmacodynamics

NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56 dim ) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment.

Exposure-Response Relationship

The exposure-response relationship and time course of pharmacodynamics of DARZALEX have not been fully characterized.

Cardiac Electrophysiology

DARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

Pharmacokinetics

Daratumumab area under the concentration-time curve (AUC) increases more than proportionally over a dosage range from 1 to 24 mg/kg (0.06 to 1.5 times the approved recommended dosage) as monotherapy or 1 to 16 mg/kg (0.06 to 1 time the approved recommended dosage) as combination therapy.

Following administration of the approved recommended dosage of DARZALEX as monotherapy or in combination therapy, the mean serum maximal concentration (C max ) was approximately 2.7 to 3-fold higher at the end of weekly dosing compared to the first dose. The mean ± standard deviation (SD) trough serum concentration (C min ) at the end of weekly dosing was 573 ± 332 µg/mL when DARZALEX was administered as monotherapy and 502 ± 196 to 607 ± 231 µg/mL when DARZALEX was administered as combination therapy. Split dosing of the first dose resulted in a different PK profile in the first day compared to single dosing; however, similar C max and C min concentrations were both predicted and observed following the administration of the second split dose on Week 1 Day 2.

When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (by the 21 st infusion). At steady state, daratumumab mean ± SD accumulation ratio for C max was 1.6 ± 0.5.

Distribution

Daratumumab volume of distribution was 4.7 ± 1.3 L as monotherapy and 4.4 ± 1.5 L as combination therapy following administration of the approved dosage.

Elimination

Daratumumab clearance decreased with increasing dose and with multiple dosing. The mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL/day and the mean ± SD estimated terminal half-life associated with linear clearance was 18 ± 9 days following administration of the approved recommended dosage of DARZALEX as monotherapy. Terminal half-life was similar when DARZALEX was administered as combination therapy.

Specific Populations

No clinically significant differences in the pharmacokinetics of daratumumab as monotherapy or as combination therapy were observed based on sex, age (31 to 93 years), mild [total bilirubin 1 to 1.5 times upper limit of normal (ULN) or aspartate aminotransaminase (AST)>ULN] and moderate (total bilirubin 1.5 to 3 times ULN and any AST) hepatic impairment, or renal impairment [Creatinine clearance (CLcr) 15–89 mL/min]. The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on daratumumab pharmacokinetics is unknown.

Body Weight

The central volume of distribution and clearance of daratumumab increased with increasing body weight.

Immunogenicity

The observed incidence of anti-drug antibody (ADA, including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of daratumumab or of other daratumumab products.

With the median DARZALEX treatment ranging from 3.3 to 48 months across 10 clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, the incidence of anti-daratumumab antibody development was 0.6% (14/2,179) and 12 patients tested positive for neutralizing antibodies. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of daratumumab products is unknown.

Nonclinical Toxicology

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.

Clinical Studies

CLINICAL STUDIES

Newly Diagnosed Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone in Patients Ineligible for Autologous Stem Cell Transplant

MAIA (NCT02252172), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medication. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45–90) years, with 44% of the patients ≥75 years of age. Fifty-two percent (52%) of patients were male, 92% White, 4% Black or African American, and 1% Asian. Three percent (3%) of patients reported an ethnicity of Hispanic or Latino. Thirty-four (34%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd. After a median follow-up of 64 months, the median PFS was 61.9 months (95% CI: 54.8, NE) in the DRd arm and 34.4 months (95% CI: 29.6, 39.2) in the Rd arm.

Figure 1: Kaplan-Meier Curve of PFS in MAIA PFS median follow-up of 28 months

Referenced Image

After a median follow-up of 56 months, MAIA demonstrated an improvement in overall survival (OS) in the DRd arm as compared to the Rd arm (HR=0.68; 95% CI: 0.53, 0.86; p=0.0013), representing a 32% reduction in the risk of death in patients treated in the DRd arm. Median OS had not been reached for either arm.

After a median follow-up of 89 months, the median OS was 90.3 months (95% CI: 80.8, NE) in the DRd arm and 64.1 months (95% CI: 56.0, 70.8) in the Rd arm.

Figure 2: Kaplan-Meier Curve of OS in MAIA OS median follow-up of 56 months

Referenced Image

Additional efficacy results from MAIA are presented in Table 23.

Table 23: Additional Efficacy Results From MAIA Based on intent-to-treat population.
DRd (N=368) Rd (N=369)
DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval
Overall response (sCR+CR+VGPR+PR) n(%) 342 (92.9%) 300 (81.3%)
p-value p-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001
Stringent complete response (sCR) 112 (30.4%) 46 (12.5%)
Complete response (CR) 63 (17.1%) 46 (12.5%)
Very good partial response (VGPR) 117 (31.8%) 104 (28.2%)
Partial response (PR) 50 (13.6%) 104 (28.2%)
CR or better (sCR + CR) 175 (47.6%) 92 (24.9%)
p-value <0.0001
VGPR or better (sCR + CR + VGPR) 292 (79.3%) 196 (53.1%)
p-value <0.0001
MRD negativity rate , Based on threshold of 10 -5 using a next-generation sequencing assay (clonoSEQ). n(%) 89 (24.2%) 27 (7.3%)
95% CI (%) (19.9%, 28.9%) (4.9%, 10.5%)
p-value p-value from Fisherʼs exact test. <0.0001
MRD negativity rate in patients with CR or better
Number of patients with CR or better N=175 N=92
MRD negativity rate n(%) 89 (50.9%) 27 (29.3%)
95% CI (%) (43.2%, 58.5%) (20.3%, 39.8%)

In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.

Combination Treatment with Bortezomib, Thalidomide and Dexamethasone in Patients Eligible for Autologous Stem Cell Transplant (ASCT)

CASSIOPEIA (NCT02541383), an open-label, randomized, active-controlled trial compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. The trial was limited to patients 65 years of age and younger. Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m 2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1–4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1–2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3–4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication.

A total of 1,085 patients were randomized: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 years (range: 22 to 65 years). The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.

Efficacy was evaluated by stringent Complete Response (sCR) rate at Day 100 post-transplant, Complete Response Rate (CR) at Day 100 post-transplant, and Progression-Free Survival (PFS).

Table 25: Efficacy Results From CASSIOPEIA at Day 100 Post-Transplant
DVTd (N=543) VTd (N=542)
D-VTd = daratumumab-bortezomib-thalidomide-dexamethasone; VTd = bortezomib-thalidomide-dexamethasone
Overall response (sCR+CR+VGPR+PR) n(%) Based on intent-to-treat population 503 (92.6%) 487 (89.9%)
Stringent complete response (sCR) 157 (28.9%) 110 (20.3%)
p-value p-value from Cochran Mantel-Haenszel Chi-Squared test. 0.0010
Complete response (CR) 54 (9.9%) 31 (5.7%)
Very good partial response (VGPR) 242 (44.6%) 282 (52.0%)
Partial response (PR) 50 (9.2%) 64 (11.8%)

CASSIOPEIA demonstrated an improvement in PFS in the DVTd arm as compared to the VTd arm; with a median follow up of 18.8 months, the median PFS had not been reached in either arm. Treatment with DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001).

Figure 5: Kaplan-Meier Curve of PFS in CASSIOPEIA based on interim analysis and the boundary for PFS was crossed.

Referenced Image

Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

POLLUX (NCT02076009), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer's prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% White, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by PFS based on IMWG criteria.

POLLUX demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing a 63% reduction in the risk of disease progression or death in patients treated with DRd. After a median follow-up of 55 months, the median PFS was 45.0 months (95% CI: 34.1, 53.9) in the DRd arm and was 17.5 months (95% CI: 13.9, 20.8) in the Rd arm.

Figure 6: Kaplan-Meier Curve of PFS in POLLUX PFS median follow-up of 13.5 months

Referenced Image

After a median follow-up of 80 months, POLLUX demonstrated an improvement in overall survival (OS) in the DRd arm as compared to the Rd arm (HR=0.73; 95% CI: 0.58, 0.91; p=0.0044), representing a 27% reduction in the risk of death in patients treated in the DRd arm. The median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm.

Figure 7: Kaplan-Meier Curve of OS in POLLUX

Referenced Image

Additional efficacy results from POLLUX are presented in Table 26.

Table 26: Additional Efficacy Results From POLLUX Based on Intent-to-treat population
DRd (N=286) Rd (N=283)
DRd = daratumumab- lenalidomide-dexamethasone; Rd = lenalidomide-dexamethasone
Overall response (sCR+CR+VGPR+PR) 261 (91.3%) 211 (74.6%)
p-value p-value from Cochran Mantel-Haenszel Chi-Squared test. <0.0001
Stringent complete response (sCR) 51 (17.8%) 20 (7.1%)
Complete response (CR) 70 (24.5%) 33 (11.7%)
Very good partial response (VGPR) 92 (32.2%) 69 (24.4%)
Partial response (PR) 48 (16.8%) 89 (31.4%)

In responders, the median time to response was 1 month (range: 0.9 to 13 months) in the DRd group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 1.4 to 18.5+ months) in the Rd group.

Combination Treatment with Pomalidomide and Dexamethasone

EQUULEUS (NCT01998971) was an open-label trial in which 103 patients with multiple myeloma who had received a prior PI and an immunomodulatory agent, received 16 mg/kg DARZALEX in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on Days 1–21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication.

The median patient age was 64 years (range: 35 to 86 years) with 8% of patients ≥75 years of age. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent (74%) of patients had received prior ASCT. Ninety-eight percent (98%) of patients received prior bortezomib treatment, and 33% of patients received prior carfilzomib. All patients received prior lenalidomide treatment, with 98% of patients previously treated with the combination of bortezomib and lenalidomide. Eighty nine percent (89%) of patients were refractory to lenalidomide and 71% refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.

Efficacy results were based on overall response rate as determined by Independent Review Committee using IMWG criteria (see Table 30 ).

Table 30: Efficacy Results for EQUULEUS
N=103
ORR = sCR+CR+VGPR+PR
CI = Confidence Interval
Overall response rate (ORR) 61 (59.2%)
95% CI (%) (49.1, 68.8)
Stringent complete response (sCR) 8 (7.8%)
Complete response (CR) 6 (5.8%)
Very good partial response (VGPR) 29 (28.2%)
Partial response (PR) 18 (17.5%)

The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months).

Monotherapy

SIRIUS (NCT01985126), was an open-label trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. In 106 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.

The median patient age was 63.5 years (range: 31 to 84 years), 49% were male and 79% were White. Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received prior autologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) and immunomodulatory agent, and 77% were refractory to alkylating agents.

Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 31 ).

Table 31: Efficacy Results for SIRIUS
N=106
ORR = sCR+CR+VGPR+PR
CI = confidence interval
Overall response rate (ORR) 31 (29.2%)
95% CI (%) (20.8, 38.9)
Stringent complete response (sCR) 3 (2.8%)
Complete response (CR) 0
Very good partial response (VGPR) 10 (9.4%)
Partial response (PR) 18 (17.0%)

The median time to response was 1 month (range: 0.9 to 5.6 months). The median duration of response was 7.4 months (range: 1.2 to 13.1+ months).

Study GEN501 (NCT00574288) was an open-label dose escalation trial evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 2 different cytoreductive therapies. In 42 patients, DARZALEX 16 mg/kg was administered with pre- and post-infusion medication. Treatment continued until unacceptable toxicity or disease progression.

The median patient age was 64 years (range: 44 to 76 years), 64% were male and 76% were White. Patients in the study had received a median of 4 prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% of patients were refractory to both, a PI and an immunomodulatory agent, and 60% of patients were refractory to alkylating agents.

Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR. The median time to response was 1 month (range: 0.5 to 3.2 months). The median duration of response was not estimable (range: 2.2 to 13.1+ months).

How Supplied/Storage & Handling

HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

DARZALEX ® (daratumumab) injection is a colorless to pale yellow, preservative-free solution for intravenous infusion.

NDC 57894-502-05 and NDC 57894-505-05 each contain one 100 mg/5 mL (20 mg/mL) single-dose vial

NDC 57894-502-20 and NDC 57894-505-20 each contain one 400 mg/20 mL (20 mg/mL) single-dose vial

Storage and Stability

Store in a refrigerator at 2°C to 8°C (36°F to 46°F).

Do not freeze or shake. Protect from light. This product contains no preservative.

Mechanism of Action

Mechanism of Action

CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T regs ) and B cells (CD38+B regs ) are decreased by daratumumab.

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