Daratumumab

Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in a positive indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist for up to 6 months after the last daratumumab infusion. It should be recognised that daratumumab bound to RBCs may mask 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.

Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may be considered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping is not impacted by daratumumab and may be performed at any time.

In the event of a planned transfusion blood transfusion centres should be notified of this interference with indirect antiglobulin tests. If an emergency transfusion is required, non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.

Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with daratumumab. HBV screening should be performed in all patients before initiation of treatment with daratumumab.

For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of daratumumab treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated.

In patients who develop reactivation of HBV while on daratumumab, suspend treatment with daratumumab and institute appropriate treatment. Resumption of daratumumab treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

Daratumumab 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. Daratumumab delay may be required to allow recovery of blood cell counts. No dose reduction of daratumumab is recommended. Consider supportive care with transfusions or growth factors.

There are no human or animal data to assess the risk of daratumumab use during pregnancy. IgG1 monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore daratumumab should not be used during pregnancy unless the benefit of treatment to the woman is considered to outweigh the potential risks to the fetus. If the patient becomes pregnant while taking this medicine, the patient should be informed of the potential risk to the fetus.

It is not known whether daratumumab is excreted into human or animal milk. Maternal IgG is excreted in human milk, but does not enter the neonatal and infant circulations in substantial amounts as they are degraded in the gastrointestinal tract and not absorbed.

The effect of daratumumab on newborns/infants is unknown. A decision should be made whether to discontinue breast-feeding or to discontinue daratumumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Women of child-bearing potential/Contraception

Women of child-bearing potential should use effective contraception during, and for 3 months after cessation of daratumumab treatment.

Fertility

No data are available to determine potential effects of daratumumab on fertility in males or females.

Daratumumab has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking daratumumab and this should be taken into account when driving or using machines.

Summary of the safety profile

The most frequent adverse reactions (≥20%) were infusion reactions, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, asthenia, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

Tabulated list of adverse reactions

The table below summarises the adverse drug reactions that occurred in patients receiving daratumumab. The data reflects exposure to daratumumab (16 mg/kg) in 2066 patients with multiple myeloma including 1910 patients who received daratumumab in combination with background regimens and 156 patients who received daratumumab as monotherapy. Post-marketing adverse reactions are also included.

In Study MMY3006, the number of CD34+ cell yield was numerically lower in the D-VTd arm compared with the VTd arm (Median: D-VTd: 6.3 × 10⁶/kg; VTd 8.9 × 10⁶/kg) and among those who completed mobilization, more patients in the D-VTd group received plerixafor compared to those in the VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitution was similar among the transplanted subjects in the D-VTd and VTd arms (D-VTd: 99.8%; VTd: 99.6%; as measured by the recovery of neutrophils >0.5 × 10⁹/L, leukocytes >1.0 × 10⁹/L, and platelets >50 × 10⁹/L without transfusion).

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions in multiple myeloma patients treated with daratumumab 16 mg/kg:

* No Grade 4.
^a Indicates grouping of terms.
^b Post-marketing adverse reaction.
^c Infusion-related reaction includes terms determined by investigators to be related to infusion, see below.

Infusion-related reactions

In clinical trials (monotherapy and combination treatments; N=2066) the incidence of any grade infusion-related reactions was 37% with the first (16 mg/kg, Week 1) infusion of daratumumab, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade ¾ infusion-related reaction with the Week 2 or subsequent infusions. The median time to onset of a reaction was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 36%. Median durations of 16 mg/kg infusions for the 1 st Week, 2 nd Week and subsequent infusions were approximately 7, 4 and 3 hours respectively. Severe infusion-related reactions included bronchospasm, dyspnoea, laryngeal oedema, pulmonary oedema, hypoxia, and hypertension. Other adverse infusion-related reactions included nasal congestion, cough, chills, throat irritation, vomiting and nausea.

When daratumumab dosing was interrupted in the setting of ASCT (Study MMY3006) for a median of 3.75 (range: 2.4; 6.9) months, upon re-initiation of daratumumab the incidence of IRRs was 11% at first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last daratumumab infusion prior to interruption due to ASCT. IRRs occurring at re-initiation of daratumumab following ASCT were consistent in terms of symptoms and severity (Grade 3/4: <1%) with those reported in previous studies at Week 2 or subsequent infusions.

In Study MMY1001, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab 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 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

Infections

In patients receiving daratumumab combination therapy, Grade 3 or 4 infections were reported as follows:

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28%

Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1-4%) and fatal infections were generally infrequent and balanced between the daratumumab containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

Key: D = daratumumab; Vd = bortezomib-dexamethasone; Rd = lenalidomide-dexamethasone; Pd = pomalidomide-dexamethasone; VMP = bortezomib-melphalan-prednisone; VTd = bortezomib-thalidomide-dexamethasone.

Haemolysis

There is a theoretical risk of haemolysis. Continuous monitoring for this safety signal will be performed in clinical studies and post-marketing safety data.

Other special populations

In the Phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, safety analysis of the subgroup of patients with an ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was consistent with the overall population.