DARZALEX® + Rd Safety Profile in Newly Diagnosed, Transplant-Ineligible MM

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The MAIA trial regimen was DARZALEX® + Rd vs Rd alone

DARZALEX® + Revlimid® (lenalidomide) + dexamethasone

Important Safety Information

CONTRAINDICATIONS

DARZALEX® is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX® can cause severe and/or serious infusion-related reactions including anaphylactic reactions. In clinical trials (monotherapy and combination: N=2066), 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). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX®. 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.

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-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, ie, 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.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. 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.

To reduce the risk of delayed infusion-related 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 is 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 and Thrombocytopenia

DARZALEX® may increase neutropenia and thrombocytopenia 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. Consider withholding DARZALEX® until recovery of neutrophils or for 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. 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.

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

The most frequently reported adverse reactions (incidence ≥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. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX® are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

Please click here to see the full Prescribing Information.

cp-60862v6

 

Most frequent adverse reactions and laboratory abnormalities reported in ≥20% of patients and with at least a 5% greater frequency in the DARZALEX® + Rd arm1*

Most frequent adverse reactions (≥20%) in the MAIA trial: DARZALEX® + Rd vs Rd alone in newly diagnosed, transplant-ineligible MM

*Adverse reactions that occurred with a frequency of ≥10% and <20%, and with at least a 5% greater frequency in the DARZALEX® + Rd arm were: headache, urinary tract infection, hyperglycemia, hypocalcemia, vomiting, chills, paresthesia, and hypertension.

Serious adverse reactions (ARs) with a 2% greater incidence in the DARZALEX® + Rd 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%).1

Most frequent laboratory abnormalities (≥20%) in the MAIA trial: DARZALEX® + Rd vs Rd alone in newly diagnosed, transplant-ineligible MM

DRd=DARZALEX® (D) + lenalidomide (R) + dexamethasone (d); MM=multiple myeloma; Rd=lenalidomide (R) + dexamethasone (d).

Revlimid® is a registered trademark of Celgene Corporation.

 

 

DARZALEX® + Rd safety profile

  • Discontinuation rates due to any adverse event: 7% with DRd vs 16% with Rd2
  • Infusion reactions (IRs) with DRd occurred in 41% of patients; 2% were Grade 3 and <1% were Grade 41
  • IRs of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion1
  • Most IRs occurred during the first infusion1

Frequency of IRs (any grade) across clinical trials (N=1530)1

40% of patients
had IRs with the first infusion
2% of patients
had IRs with the second infusion
Cumulatively, 4% of patients had IRs with subsequent infusions

 

In clinical trials (monotherapy and combination treatments; N=1530)

Most infusion reactions occurred during the first infusion1

  • For 40% of patients, infusion reactions (any grade) occurred with the first infusion; for 2% of patients with the second infusion; and cumulatively, for 4% of patients with subsequent infusions1
  • Median time to onset of an infusion reaction was 1.5 hours (range: 0 to 72.8 hours)1
  • Incidence of infusion modification due to reactions was 37%1
  • DARZALEX® can cause severe infusion reactions. Severe infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions were nasal congestion, cough, chills, throat irritation, vomiting, and nausea1

 

Management of infusion reactions

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® as outlined below.1

Recommended management of infusion reactions1
Infusion reaction grade Dose interruptions/modifications
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
Grade 3
(severe)
Once symptoms resolve:
  • Consider restarting 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 appropriate

In the event of recurrence of Grade 3 symptoms:

  • Repeat the procedure above

If the patient experiences a third occurrence of a Grade 3 or higher infusion reaction:

  • Permanently discontinue DARZALEX®
Grade 4
(life threatening)
Permanently discontinue DARZALEX®

Infusion reactions of any grade or severity may require management by interruption, modification, and/or discontinuation of the infusion.1

 

Interference with serological testing1

DARZALEX® binds to CD38 found on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test) that may persist for up to 6 months after the last DARZALEX® infusion.

Reminders

  • Type and screen patients before starting DARZALEX®
  • Inform blood banks when a patient is on DARZALEX®
  • Identify any DARZALEX®-treated blood samples
  • Ask patients to tell other healthcare professionals that they have taken DARZALEX®

Find out more about interference with serological testing for patients being treated with DARZALEX®

Provide this document to patients to let healthcare professionals know that the patient is being treated with DARZALEX®