In Combination With Rd or Vd for Multiple Myeloma Patients at First Relapse

DARZALEX® is indicated 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.

Rd = lenalidomide and dexamethasone.

Vd = bortezomib and dexamethasone.

Greater than 60% reduction in the risk of disease progression or death with DARZALEX® plus Rd or Vd vs either therapy alone.
  • DARZALEX® + Rd: 63%
    risk reduction (P<0.0001;
    HR = 0.37; 95% CI: 0.27, 0.52)
  • DARZALEX® + Vd: 61%
    risk reduction (P<0.0001;
    HR = 0.39; 95% CI: 0.28, 0.53)

First-in-class immunotherapy that binds to CD38

Approval based on 2 randomized, open-label, multicenter, active-control phase 3 trials involving 1067 patients

Established safety profile

Important Safety Information

Warnings and precautions include: infusion reactions, interference with serological testing, neutropenia, thrombocytopenia, and interference with determination of complete response

In patients who received DARZALEX® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were: pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were: upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).

 

DARZALEX® is the first and only CD38-directed monoclonal antibody (mAb)

MECHANISM OF ACTION

DARZALEX® (daratumumab) is a first-in-class monoclonal antibody that targets CD381

CD38 is expressed on hematopoietic cells and other cell types and tissues, and is over-expressed on multiple myeloma cells

  • DARZALEX® inhibits tumor cell growth through immune-mediated, direct on-tumor, and immunoregulatory actions.1 DARZALEX® may also have an effect on normal cells

DARZALEX® is the first CD38-targeted monoclonal antibody (mAb)

CLINICAL EFFICACY OF DARZALEX® + Rd vs Rd ALONE

POLLUX study design

POLLUX trial: DARZALEX® (daratumumab) in combination with Rd vs Rd alone1

  • POLLUX was an open-label, randomized, active-controlled Phase 3 trial1,2
Prior Therapy1 Patients
Immunomodulatory agent 55%
PI 86%
Both a PI and an immunomodulatory agent 44%
Autologous stem cell transplant 63%
  • Baseline demographics were similar between arms: median age 65 years (range: 34 to 89), 59% male, 69% Caucasian, 18% Asian, and 3% African American1
  • The primary endpoint was PFS,* and the median follow-up was 13.5 months1,2

PFS = progression-free survival; PI = proteasome inhibitor; Rd = lenalidomide and dexamethasone.

*Efficacy was evaluated by PFS based on International Myeloma Working Group criteria.

Daratumumab (DARZALEX®) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, is recommended by the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) as a preferred Category 1† therapeutic option for previously treated multiple myeloma‡

†Category 1 = based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

‡Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed April 6, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org.
The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

DARZALEX® + Rd demonstrated superior efficacy vs Rd alone

Significant improvement in progression-free survival using DARZALEX®-based triplet therapy1

CI = confidence interval; HR = hazard ratio; PFS = progression-free survival; Rd = lenalidomide and dexamethasone.

Median progression-free survival had not yet been reached with DARZALEX® + Rd triplet therapy vs 18.4 months with Rd alone1

Complete response rate more than doubled with DARZALEX® + Rd vs Rd alone

Almost all (91%) patients responded to DARZALEX® + Rd1

CR = complete response; ORR = overall response rate; PR = partial response; Rd = lenalidomide and dexamethasone; sCR = stringent complete response; VGPR = very good partial response.

Deeper and sustained responses were demonstrated with DARZALEX® + Rd vs Rd alone1

  • With DARZALEX® + Rd, median time to response was 1 month (range: 0.9 to 13 months), median time to very good partial response or better was 3.7 months (95% confidence interval [CI]: 3.0, 3.8), and median time to complete response or better was 13.2 months (95% CI: 10.6, not estimable)1,2,4

Median duration of response was not yet reached with DARZALEX® + Rd (range: 1+ to 19.8+ months) vs 17.4 months with Rd alone (range: 1.4 to 18.5+ months), at a median follow-up of 13.5 months1

SAFETY PROFILE OF DARZALEX® + Rd vs Rd ALONE

Established safety profile with DARZALEX® (daratumumab) + Rd

Adverse reactions with incidence ≥10%1
DARZALEX® + Rd
n=283		 Rd
n=281
Adverse reaction Any grade (%) Grade 3 (%) Grade 4 (%) Any grade (%) Grade 3 (%) Grade 4 (%)
Infusion reactions 48 5 0 0 0 0
Gastrointestinal disorders
Diarrhea 43 5 0 25 3 0
Nausea 24 1 0 14 0 0
Vomiting 17 1 0 5 1 0
General disorders and administration site conditions
Fatigue 35 6 <1 28 2 0
Pyrexia 20 2 0 11 1 0
Infections and infestations
Upper respiratory tract infection* 65 6 <1 51 4 0
Musculoskeletal and connective tissue disorders
Muscle spasms 26 1 0 19 2 0
Nervous system disorders
Headache 13 0 0 7 0 0
Respiratory, thoracic, and mediastinal disorders
Cough† 30 0 0 15 0 0
Dyspnea‡ 21 3 <1 12 1 0

Rd = lenalidomide and dexamethasone.

*Upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection.

†Cough, productive cough, allergic cough.

‡Dyspnea, dyspnea exertional.

Note: Adverse reactions that occurred in ≥10% of patients and with at least 5% greater frequency in the DARZALEX® + Rd arm are listed. In addition, serious adverse events are listed if there was at least a 2% greater incidence in the DARZALEX® + Rd arm compared to the Rd arm.

  • Infusion reaction includes terms determined by the investigators to be related to the infusion. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other any-grade adverse infusion reactions (any grade; ≥5%) were nasal congestion, cough, chills, throat irritation, and vomiting1

Safety demonstrated in combination with Rd

  • The most frequent adverse reactions (ARs; ≥20%) with DARZALEX® + Rd were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, cough, and dyspnea1
    • Serious ARs with at least a 2% greater incidence in the DARZALEX® + Rd arm compared to the Rd arm were pneumonia (DARZALEX® + Rd 12% vs Rd 10%), upper respiratory tract infection (DARZALEX® + Rd 7% vs Rd 4%), influenza and pyrexia (DARZALEX® + Rd 3% vs Rd 1% for each)

Important Safety Information

Infusion Reactions

  • DARZALEX® can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.
  • Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.
  • To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. 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.

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. The determination of a patient’s ABO and Rh blood type are not impacted. 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®.

Neutropenia

  • DARZALEX® may increase neutropenia induced by background therapy. 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. DARZALEX® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors.

Thrombocytopenia

  • DARZALEX® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with transfusions.

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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions

  • In patients who received DARZALEX® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were: pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).
  • In patients who received DARZALEX® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were: upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).
Treatment-emergent hematology laboratory abnormalities1
DARZALEX® + Rd
n=283		 Rd
n=281
Any grade (%) Grade 3 (%) Grade 4 (%) Any grade (%) Grade 3 (%) Grade 4 (%)
Anemia 52 13 0 57 19 0
Thrombocytopenia 73 7 6 67 10 5
Neutropenia 92 36 17 87 32 8
Lymphopenia 95 42 10 87 32 6

Rd = lenalidomide and dexamethasone.

  • Grade 3/4 infections were similar between study arms: 28% vs 23% with DARZALEX® + Rd vs Rd, respectively1
  • Discontinuation rates due to ARs with DARZALEX® + Rd were similar to Rd alone (7% vs 8%, respectively)1

DOSING AND ADMINISTRATION IN THE POLLUX STUDY

POLLUX: DARZALEX® (daratumumab) + Rd dosing

Dosing frequency of DARZALEX® decreases throughout the course of therapy1

  • DARZALEX® is given as an intravenous (IV) infusion at 16 mg/kg of body weight
  • Lenalidomide is given orally on days 1 to 21 of each cycle*
  • Dexamethasone 40 mg is given orally or IV weekly†
    • 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
Cycles 1–2 (each lasting 28 days)
Total of 8 DARZALEX® doses
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
DARZALEX®
lenalidomide Rest
dexamethasone
Cycles 3–6 (each lasting 28 days)
Total of 8 DARZALEX® doses
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
DARZALEX®
lenalidomide Rest
dexamethasone
Cycles 7+ (each lasting 28 days)
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
DARZALEX®
lenalidomide Rest
dexamethasone

Continue DARZALEX® + Rd until disease progression or unacceptable toxicity

Rd = lenalidomide plus dexamethasone.

*Please refer to the lenalidomide Prescribing Information for more detailed information about lenalidomide dosing.

†Dexamethasone dosing may be modified for various patient populations. Please see the DARZALEX® Prescribing Information for more information.



  • DARZALEX® should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur
  • If a planned dose of DARZALEX® is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval1

CLINICAL EFFICACY OF DARZALEX® + Vd vs Vd ALONE

CASTOR study design

CASTOR trial: DARZALEX® (daratumumab) in combination with Vd vs Vd alone

  • CASTOR was an open-label, randomized, active-controlled Phase 3 trial1,3
Prior Therapy1,3 Patients
PI 69%
Immunomodulatory agent 76%
Both a PI and an immunomodulatory agent 48%
Autologous stem cell transplant 61%
  • Baseline demographics were similar between arms: median age 64 years (range: 30 to 88), 57% male, 87% Caucasian, 5% Asian, and 4% African American1
  • The primary endpoint was PFS,* and the median follow-up was 7.4 months1,3

PI = proteasome inhibitor; PFS = progression-free survival; Vd = bortezomib and dexamethasone.

*Efficacy was evaluated by PFS based on International Myeloma Working Group criteria.

Daratumumab (DARZALEX®) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, is recommended by the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) as a preferred Category 1† therapeutic option for previously treated multiple myeloma‡

†Category 1 = based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

‡Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed April 6, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org.
The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

DARZALEX® + Vd demonstrated superior efficacy vs Vd alone

Significant improvement in progression-free survival using DARZALEX®-based triplet therapy1

CI = confidence interval; HR = hazard ratio; PFS = progression-free survival; Vd = bortezomib and dexamethasone.

Median progression-free survival had not yet been reached with DARZALEX® + Vd triplet therapy vs 7.2 months with Vd alone1

Complete response rate more than doubled with DARZALEX® + Vd vs Vd alone

The majority (79%) of patients responded to DARZALEX® + Vd1

CR = complete response; ORR = overall response rate; PR = partial response; sCR = stringent complete response;

Vd = bortezomib and dexamethasone; VGPR = very good partial response.

Deeper and sustained responses were demonstrated with DARZALEX® + Vd vs Vd alone1

  • With DARZALEX® + Vd, median time to response was 0.8 months (range: 0.7 to 4 months), median time to very good partial response or better was 3.5 months (95% confidence interval [CI]: 2.8, 4.2), and median time to complete response or better was not yet reached (95% CI: 12.0, not estimable)1,4

Median duration of response was not yet reached with DARZALEX® + Vd (range: 1.4+ to 14.1+ months) vs 7.9 months with Vd alone (range: 1.4+ to 12+ months), at a median follow-up of 7.4 months1

SAFETY PROFILE OF DARZALEX® + Vd vs Vd ALONE

Established safety profile with DARZALEX® (daratumumab) + Vd

Adverse reactions with incidence ≥10%1
DARZALEX® + Vd
n=243		 Vd
n=237
Adverse reaction Any grade (%) Grade 3 (%) Grade 4 (%) Any grade (%) Grade 3 (%) Grade 4 (%)
Infusion reactions 45 9 0 0 0 0
Gastrointestinal disorders
Diarrhea 32 3 <1 22 1 0
Vomiting 11 0 0 4 0 0
General disorders and administration site conditions
Edema peripheral* 22 1 0 13 0 0
Pyrexia 16 1 0 11 1 0
Infections and infestations
Upper respiratory tract infection† 44 6 0 30 3 <1
Nervous system disorders
Peripheral sensory neuropathy 47 5 0 38 6 <1
Respiratory, thoracic, and mediastinal disorders
Cough‡ 27 0 0 14 0 0
Dyspnea§ 21 4 0 11 1 0

Vd = bortezomib and dexamethasone.

*Edema peripheral, edema, generalized edema, peripheral swelling.

†Upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection.

‡Cough, productive cough, allergic cough.

§Dyspnea, dyspnea exertional.

Note: Adverse reactions that occurred in ≥10% of patients and with at least 5% greater frequency in the DARZALEX® + Vd arm are listed. In addition, serious adverse events are listed if there was at least a 2% greater incidence in the DARZALEX® + Vd arm compared to the Vd arm.

  • Infusion reaction includes terms determined by investigators to be related to infusion. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; ≥5%) were nasal congestion, cough, chills, throat irritation, and vomiting1

Safety demonstrated in combination with Vd

  • The most frequent adverse reactions (ARs; >20%) with DARZALEX® + Vd were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough, and dyspnea1
    • Serious ARs with at least a 2% greater incidence in the DARZALEX® + Vd arm compared to the Vd arm were upper respiratory tract infection (DARZALEX® + Vd 5% vs Vd 2%), diarrhea and atrial fibrillation (DARZALEX® + Vd 2% vs Vd 0% for each)

Important Safety Information

Infusion Reactions

  • DARZALEX® can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.
  • Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.
  • To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. 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.

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. The determination of a patient’s ABO and Rh blood type are not impacted. 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®.

Neutropenia

  • DARZALEX® may increase neutropenia induced by background therapy. 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. DARZALEX® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors.

Thrombocytopenia

  • DARZALEX® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with transfusions.

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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions

  • In patients who received DARZALEX® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were: pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).
  • In patients who received DARZALEX® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were: upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).
Treatment-emergent hematology laboratory abnormalities1
DARZALEX® + Vd
n=243		 Vd
n=237
Any grade (%) Grade 3 (%) Grade 4 (%) Any grade (%) Grade 3 (%) Grade 4 (%)
Anemia 48 13 0 56 14 0
Thrombocytopenia 90 28 19 85 22 13
Neutropenia 58 12 3 40 5 <1
Lymphopenia 89 41 7 81 24 3

Vd = bortezomib and dexamethasone.

  • Grade 3/4 infections were similar between study arms: 21% vs 19% with DARZALEX® + Vd vs Vd, respectively1
  • Discontinuation rates due to ARs with DARZALEX® + Vd were similar to Vd alone (7% vs 9%, respectively)1

DOSING AND ADMINISTRATION IN THE CASTOR STUDY

CASTOR: DARZALEX® (daratumumab) + Vd dosing

Dosing frequency of DARZALEX® decreases throughout the course of therapy1

  • DARZALEX® is given as an intravenous (IV) infusion after dilution at 16 mg/kg of body weight
  • Bortezomib is administered by subcutaneous or IV injection on days 1, 4, 8, and 11 of each cycle for a total of 8 cycles*
  • Dexamethasone 20 mg is given orally once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle for a total of 8 cycles†
    • On DARZALEX® infusion days, dexamethasone 20 mg was given as a pre-infusion medication and was continued as a pre-medication after Vd discontinuation
Cycles 1–3 (each lasting 21 days)
Total of 9 DARZALEX® doses
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
DARZALEX®
bortezomib Rest
dexamethasone
Cycles 4–8 (each lasting 21 days)
Total of 5 DARZALEX® doses
Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
DARZALEX®
bortezomib Rest
dexamethasone

Cycle 9+ (each lasting 28 days)

Continue DARZALEX® once every 4 weeks until disease progression or unacceptable toxicity1,3

Note: Bortezomib dosing should be stopped after 8 cycles. Dexamethasone 20 mg was continued as a pre-infusion medication after Vd discontinuation.1

*Please refer to the bortezomib Prescribing Information for more detailed information about twice-weekly bortezomib dosing.

†Dexamethasone dosing may be modified for various patient populations. Please see the DARZALEX® Prescribing Information for more information.



  • DARZALEX® should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion reactions if they occur
  • If a planned dose of DARZALEX® is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval1

DARZALEX® INFUSION

Infusion rates for DARZALEX® (daratumumab)

Slower rate of infusion for the first DARZALEX® dose is recommended, as infusion reactions are more likely to occur with the first infusion1

Infusion rates for DARZALEX® administration1
Dilution volume Initial rate
(first hour)		 Rate
increment*		 Maximum rate
First infusion 1000 mL 50 mL/hour 50 mL/hour
every hour		 200 mL/hour
Second infusion† 500 mL 50 mL/hour 50 mL/hour
every hour		 200 mL/hour
Subsequent infusions‡ 500 mL 100 mL/hour 50 mL/hour
every hour		 200 mL/hour

*Consider incremental escalation of the infusion rate only in the absence of infusion reactions.

†Use a dilution volume of 500 mL only if there are no Grade 1 (mild) or greater infusion reactions during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion.

‡Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if there are no Grade 1 (mild) or greater infusion reactions during a final infusion rate of ≥100 mL/hour in the first 2 infusions. Otherwise, continue to use instructions for the second infusion.

Median infusion duration decreased considerably after the first infusion1

  • 1st infusion was 7.0 hours
  • 2nd infusion was 4.3 hours
  • Subsequent infusions were 3.5 hours

Prophylaxis for herpes zoster reactivation1

  • Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX® and continue for 3 months following treatment

Pre- and post-infusion medications and dose modifications1

  • To reduce the risk of infusion reactions, administration of pre- and post-infusion medications is recommended
  • No dose reductions of DARZALEX® are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of hematological toxicity

Almost half (47%) of patients experienced an infusion reactionⅠⅠ

Infusion reactions reported were predominantly Grade 1 or 21

  • For 46% of patients, infusion reactions (any grade) occurred with the first infusion; for 2% of patients, with the second infusion; and for 4% of patients, with subsequent infusionsǁ
  • Median time to onset of an infusion reaction was 1.5 hours (range: 0.02 to 72.8 hours)1
  • Incidence of infusion modification due to reactions was 41%1
  • DARZALEX® can cause severe infusion reactions. Severe (Grade 3) infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions (any grade; ≥5%) were nasal congestion, cough, chills, throat irritation, and vomiting1
  • For infusion reactions of any grade/severity, immediately interrupt the DARZALEX® infusion and manage symptoms. Management of infusion reactions may further require reduction in the rate of infusion or treatment discontinuation of DARZALEX®1

ǁInfusion reaction information includes patients in DARZALEX® monotherapy and combination therapy clinical trials (N=717).

Infusion reactions of any grade or severity may be managed by interruption, modification, and/or discontinuation of the infusion1

Pre- and post-infusion medications are recommended1

Pre-infusion medications1

To reduce the risk of infusion reactions, administer approximately 1 to 3 hours prior to every infusion as follows:

  • Intravenous (IV) dexamethasone 20 mg prior to the first infusion and IV or oral dexamethasone 20 mg prior to subsequent infusions
  • Oral antipyretics (acetaminophen 650 to 1000 mg), plus
  • Oral or IV antihistamine (diphenhydramine 25 to 50 mg or equivalent)

Note: On DARZALEX® infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication.
For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX® pre-infusion medication.

Post-infusion medications1

To reduce the risk of delayed infusion reactions, administer after every infusion as follows:

  • Oral corticosteriod (≤20 mg methylprednisolone or equivalent); however, if a background regimen-specific corticosteroid (eg, dexamethasone) is administered the day after the DARZALEX® infusion, additional post-infusion medications may not be needed

Note: For patients with a history of obstructive pulmonary disorder, consider including short- and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 infusions, if the patient experiences no major infusion reactions, these additional inhaled post-infusion medications may be discontinued.

COMPANY:
Janssen Biotech, Inc.
PHARMACOLOGIC CLASS:
CD38-directed monoclonal antibody.
ACTIVE INGREDIENT:
Daratumumab.
INDICATION:
DARZALEX® is indicated:
  • in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least 1 prior therapy
  • as monotherapy, for the treatment of patients with multiple myeloma who have received at least 3 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
DOSING AND
ADMINISTRATION
IN ADULTS:
Premedicate with corticosteroids (long- or intermediate-acting), oral antipyretics, oral or IV antihistamines 1–3 hours prior to every infusion, and administer oral corticosteroids post-infusion. Give only as an IV infusion after dilution. Monotherapy and combination therapy with lenalidomide and dexamethasone: 16 mg/kg actual body weight given as an IV infusion weekly at Weeks 1–8, every 2 weeks at Weeks 9–24, then every 4 weeks at Week 25 onward until disease progression. Combination therapy with bortezomib and dexamethasone: 16 mg/kg actual body weight given as an IV infusion weekly at Weeks 1–9, every 3 weeks at Weeks 10–24, then every 4 weeks at Week 25 onward until disease progression. Infusion rates: administer only as an IV infusion after dilution at the infusion rate described in full labeling. Consider incremental escalation of the infusion rate only in the absence of infusion reactions. Management of infusion reactions, pre- and post-infusion medications, others: see full labeling. Prophylaxis for herpes zoster reactivation: initiate antiviral prophylaxis within 1 week after starting therapy and continue for 3 months after treatment.
WARNINGS/PRECAUTIONS:

Infusion Reactions:
DARZALEX® can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support. Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. 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.

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. The determination of a patient’s ABO and Rh blood type are not impacted. 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®.

Neutropenia:
DARZALEX® may increase neutropenia induced by background therapy. 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. DARZALEX® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors.

Thrombocytopenia:
DARZALEX® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with transfusions.

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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Use in Specific Populations:
Effect of severe hepatic impairment is unknown. Pregnancy and nursing mothers: see full labeling. Females of reproductive potential should use effective contraception during treatment and for 3 months after cessation. Safety and effectiveness of DARZALEX® in pediatric patients have not been established. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients.

ADVERSE REACTIONS:

The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were: infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, muscle spasms, back pain, pyrexia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.

DRUG INTERACTIONS:

Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide or bortezomib with DARZALEX® did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX® with bortezomib did not affect the pharmacokinetics of bortezomib.
GENERIC AVAILABILITY:
No
HOW SUPPLIED:
Single-dose vial—1: 100 mg/5 mL; 400 mg/20 mL.
MPR Monograph © 2017 Haymarket Media, Inc. All rights reserved.
REFERENCES
  1. DARZALEX® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
  2. Dimopoulos MA, Oriol A, Nahi H, et al; the POLLUX investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016:375(14):1319-1331.
  3. Palumbo A, Chanan-Khan A, Weisel K, et al; the CASTOR investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
  4. Data on file. Janssen Biotech, Inc.

Contact Janssen CarePath at 1-844-55DARZA (1-844-553-2792), Monday through Friday, 8:00 AM to 8:00 PM ET, to learn about cost support options.

For more information, visit: www.darzalexhcp.com

© Janssen Biotech, Inc. 2017

1/17

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This Cancer Therapy Advisor Prescribing Alert® is produced as a basic reminder of important information for healthcare professionals. Readers are advised to consult manufacturers and specialists if questions arise about specific products, treatments, or diseases. The publisher and editors do not assume liability for any errors or omissions. MPR and Prescribing Alert are registered trademarks of Haymarket Media, Inc.

© 2017 Haymarket Media, Inc.

Privacy Policy

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS

Infusion Reactions - DARZALEX® can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX® infusions. 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.

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. The determination of a patient’s ABO and Rh blood type are not impacted. 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®.

Neutropenia - DARZALEX® may increase neutropenia induced by background therapy. 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. DARZALEX® dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX® is recommended. Consider supportive care with growth factors.

Thrombocytopenia - DARZALEX® may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX® dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX® is recommended. Consider supportive care with transfusions.

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. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions - In patients who received DARZALEX® in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX® in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).

DRUG INTERACTIONS

Effect of Other Drugs on Daratumumab: The coadministration of lenalidomide or bortezomib with DARZALEX® did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX® with bortezomib did not affect the pharmacokinetics of bortezomib.

See full Prescribing Information

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