4.8     Undesirable effects

Summary of the safety profile

The most frequent adverse reactions of any grade (≥20 % patients) with daratumumab (either intravenous or subcutaneous formulations) when administered either as monotherapy or combination treatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anaemia, oedema peripheral, peripheral sensory neuropathy and upper respiratory tract infection. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration, diarrhoea and atrial fibrillation.

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Infections

In patients receiving DARZALEX subcutaneous formulation as monotherapy, incidence of infections was similar between DARZALEX subcutaneous formulation (52.9%) versus intravenous daratumumab groups (50.0%). Additionally, Grade 3 or 4 infections also occurred at similar frequencies between DARZALEX subcutaneous formulation (11.7%) and intravenous daratumumab (14.3%). Most infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies.

In patients receiving intravenous daratumumab combination therapy, Grade 3 or 4 infections were reported with intravenous daratumumab combinations and background therapies (as follows:

Relapsed/refractory patient studies: DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; D‑VMP: 23%, VMP: 15%; 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 active controlled studies, Ddiscontinuations from treatment due to infections were reportedoccurred in 1-4% to 5% of patients. Fatal infections were generally balanced between the intravenous daratumumab containing regimens and active control arms (<2%) in the controlled studies and were primarily due to pneumonia and sepsis.

In patients receiving intravenous daratumumab combination therapy, fatal infections (Grade 5) were reported as follows:

Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%

Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.

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

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Elderly patients

Of the 3207 patients who received daratumumab (n=490 subcutaneous; n=2717 intravenous) at the recommended dose, 38% were 65 to 75 years of age, and 17% were 75 years of age or older. No overall differences in effectiveness were observed based on age. The incidence of serious adverse reactions was higher in older than in younger patients. Among patients with relapsed and refractory multiple myeloma (n=1827), the most common serious adverse reactions that occurred more frequently in elderly (≥65 years of age) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=777), the most common serious adverse reaction that occurred more frequently in elderly (≥75 years of age) was pneumonia.

Common (may affect up to 1 in 10 people):

• irregular heart beat (atrial fibrillation)
• build up of fluid in the lungs making you short of breath
• flu
• urinary tract infection
• severe infection throughout the body (sepsis)
• dehydration
• high level of sugar in the blood
• low level of calcium in the blood
• inflamed pancreas

5.1          Pharmacodynamic properties

Immunogenicity

In patients treated with subcutaneous daratumumab in clinical trials, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies. The incidence of treatment‑emergent anti‑daratumumab antibodies for DARZALEX subcutaneous formulation treatment was low, with 1 out of 451 patients tested positive for anti‑drug antibodies. The 1 patient in monotherapy that was positive for anti‑daratumumab antibody also had transient neutralising antibodies. There were no treatment‑emergent anti‑daratumumab antibody positive patients in combination therapies study. The anti‑daratumumab antibodies and neutralising antibodies did not appear to impact daratumumab exposures.

However, the employed assay has limitations in detecting anti‑daratumumab antibodies in the presence of high concentrations of daratumumab. Therefore, the incidence of antibody development might not have been reliably determined.

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