Daratumumab

CD38 is a transmembrane glycoprotein involved in cell adhesion, signalling and enzymatic activity. It is expressed at high levels on multiple myeloma cells and at lower, variable levels on other cell types and tissues. Daratumumab binds a unique epitope on CD38 with high affinity and directs the immune system against the cells that carry it.

Mechanism of Action

• Immune effector killing: through its Fc region, daratumumab activates complement (complement-dependent cytotoxicity), natural killer cells (antibody-dependent cell-mediated cytotoxicity) and macrophages (antibody-dependent cellular phagocytosis), so that CD38-expressing tumour cells are destroyed.
• Apoptosis: after Fc-mediated cross-linking, it induced apoptosis of tumour cells in vitro.
• Immunomodulation: it depletes CD38-positive myeloid-derived suppressor cells, regulatory T cells and regulatory B cells. CD4+ and CD8+ T-cell counts rose in blood and bone marrow during treatment, and T-cell clonality increased, suggesting immune effects that may add to the clinical response.
• Enzymatic effects: it inhibits the cyclase and stimulates the hydrolase activity of CD38; the clinical relevance of these effects is not well understood.
• Red blood cells: CD38 is also present on red blood cells, which is why daratumumab interferes with blood compatibility tests.

Pharmacokinetics

• Absorption: given intravenously. Between 1 and 24 mg/kg, AUC increased more than in proportion to dose and clearance fell, consistent with target-mediated disposition that saturates as CD38 is occupied. At the end of weekly dosing at 16 mg/kg, the mean peak serum concentration was 915 µg/mL, about 2.9 times that after the first infusion, and the mean trough 573 µg/mL. The subcutaneous form reaches similar exposure (peak about 592 µg/mL compared with 688 µg/mL intravenously, with almost identical AUC).
• Distribution: initially mainly within the plasma; volume of distribution about 4.7 L with monotherapy and 4.4 L with combination therapy.
• Metabolism: broken down by proteolytic enzymes into small peptides and amino acids; renal excretion and liver-enzyme metabolism of the intact antibody are unlikely to be major routes.
• Elimination: clearance falls with higher and repeated doses, possibly also as tumour burden decreases. The half-life after the first 16 mg/kg dose was about 9 days; once target-mediated clearance is saturated with repeated dosing, the terminal half-life is about 18 days (about 20 days for the subcutaneous form).
• Special populations: population analyses support no dose adjustment for renal or hepatic impairment or for age.

Intravenous Darzalex is indicated in adults with multiple myeloma:

• Newly diagnosed, not eligible for autologous stem cell transplant: in combination with lenalidomide and dexamethasone, or with bortezomib, melphalan and prednisone.
• Newly diagnosed, eligible for autologous stem cell transplant: in combination with bortezomib, thalidomide and dexamethasone.
• After at least one prior therapy: in combination with lenalidomide and dexamethasone, or with bortezomib and dexamethasone.
• Relapsed and refractory disease (monotherapy): in patients whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and whose disease progressed on the last therapy.

Darzalex is also available as a subcutaneous solution for injection (1,800 mg) with its own SmPC, which in adults is indicated for:

• Newly diagnosed multiple myeloma, not eligible for autologous stem cell transplant: in combination with lenalidomide and dexamethasone, or with bortezomib, melphalan and prednisone.
• Newly diagnosed multiple myeloma: in combination with bortezomib, lenalidomide and dexamethasone.
• Newly diagnosed multiple myeloma, eligible for autologous stem cell transplant: in combination with bortezomib, thalidomide and dexamethasone.
• Multiple myeloma after at least one prior therapy: in combination with lenalidomide and dexamethasone, or with bortezomib and dexamethasone.
• Multiple myeloma, with pomalidomide and dexamethasone: after one prior therapy that included a proteasome inhibitor and lenalidomide in patients refractory to lenalidomide, or after at least two prior therapies that included lenalidomide and a proteasome inhibitor, with disease progression on or after the last therapy.
• Relapsed and refractory multiple myeloma (monotherapy): in patients whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and whose disease progressed on the last therapy.
• Smouldering multiple myeloma (monotherapy): in patients at high risk of developing multiple myeloma.
• Light-chain (AL) amyloidosis: in combination with cyclophosphamide, bortezomib and dexamethasone, for newly diagnosed systemic AL amyloidosis.

• Hypersensitivity to daratumumab or to any of the excipients.

The data come from 2,066 patients with multiple myeloma treated at 16 mg/kg, 1,910 of them in combination regimens and 156 with monotherapy. The most frequent side effects (at least 20% of patients) were infusion-related reactions, fatigue, nausea, diarrhoea, constipation, pyrexia, dyspnoea, cough, neutropenia, thrombocytopenia, anaemia, peripheral oedema, asthenia, peripheral neuropathy, upper respiratory tract infection, musculoskeletal pain and COVID-19.

Very common (≥1/10): upper respiratory tract infection, COVID-19, pneumonia, bronchitis, neutropenia, thrombocytopenia, anaemia, lymphopenia, leukopenia, decreased appetite, hypokalaemia, insomnia, peripheral neuropathy, headache, paraesthesia, dizziness, hypertension, cough, dyspnoea, constipation, diarrhoea, nausea, vomiting, abdominal pain, rash, musculoskeletal pain, arthralgia, muscle spasms, peripheral oedema, fatigue, pyrexia, asthenia, infusion-related reactions.

Common (≥1/100 to <1/10): urinary tract infection, sepsis, cytomegalovirus infection, hypogammaglobulinaemia, hyperglycaemia, hypocalcaemia, dehydration, syncope, atrial fibrillation, hypotension, pulmonary oedema, pancreatitis, pruritus, chills, weight decreased.

Uncommon (≥1/1,000 to <1/100): hepatitis B virus reactivation.

Rare (≥1/10,000 to <1/1,000): anaphylactic reaction.

Severe (grade 3–4) neutropenia occurred in 39% of patients, thrombocytopenia in 19%, anaemia in 12%, and pneumonia and lymphopenia in 11% each. Infusion-related reactions affected 37% of patients at the first infusion, 2% at the second and 6% cumulatively at later infusions. Serious adverse reactions included sepsis, pneumonia, bronchitis, upper respiratory tract infection, pulmonary oedema, pyrexia, dehydration, diarrhoea, atrial fibrillation and syncope; fatal infections were mainly due to pneumonia and sepsis. Serious reactions were more frequent in older patients.

• No metabolic interactions expected: no interaction studies have been performed. As an IgG1κ antibody, daratumumab is not eliminated by drug-metabolising enzymes and is not expected to alter them.
• Myeloma medicines: no clinically relevant pharmacokinetic interaction with lenalidomide, pomalidomide, thalidomide, bortezomib or dexamethasone.
• Blood compatibility tests (indirect Coombs test): daratumumab binds CD38 on red blood cells and interferes with antibody screening and cross-matching. The interference can be removed by treating reagent red cells with dithiothreitol (DTT) or by other validated methods. Because the Kell blood group is also sensitive to DTT, Kell-negative units should be supplied after alloantibodies have been ruled out or identified; phenotyping or genotyping are alternatives.
• Serum protein electrophoresis and immunofixation: daratumumab can be detected by these tests and cause false-positive results in patients with IgG kappa myeloma protein, which affects the assessment of complete response by IMWG criteria.

The intravenous form of Darzalex is given by a healthcare professional in an environment where resuscitation facilities are available. Medicines are given before and after infusions to reduce the risk of infusion-related reactions. The doses and schedules below are for the intravenous form; the subcutaneous form is described at the end of this section.

With Lenalidomide and Dexamethasone, and as Monotherapy (4-Week Cycles)

• 16 mg/kg body weight by intravenous infusion: weekly in weeks 1–8 (8 doses), every 2 weeks in weeks 9–24 (8 doses), then every 4 weeks from week 25 until disease progression.
• Dexamethasone is given at 40 mg per week (20 mg per week for patients over 75 years).

With Bortezomib, Melphalan and Prednisone (6-Week Cycles)

• 16 mg/kg body weight: weekly in weeks 1–6 (6 doses), every 3 weeks in weeks 7–54 (16 doses), then every 4 weeks from week 55 until disease progression.
• Bortezomib is given twice weekly in weeks 1, 2, 4 and 5 of the first 6-week cycle, then once weekly in weeks 1, 2, 4 and 5 for eight more 6-week cycles.

With Bortezomib, Thalidomide and Dexamethasone (Transplant-Eligible, 4-Week Cycles)

• Induction: 16 mg/kg weekly in weeks 1–8 (8 doses), then every 2 weeks in weeks 9–16 (4 doses). Treatment stops for high-dose chemotherapy and the stem cell transplant.
• Consolidation: after the transplant, every 2 weeks in weeks 1–8 (4 doses).
• Dexamethasone 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2; 40 mg on days 1–2 and 20 mg on days 8, 9, 15 and 16 of cycles 3 and 4; 20 mg on days 1, 2, 8, 9, 15 and 16 of cycles 5 and 6.

With Bortezomib and Dexamethasone (3-Week Cycles)

• 16 mg/kg: weekly in weeks 1–9 (9 doses), every 3 weeks in weeks 10–24 (5 doses), then every 4 weeks from week 25 until disease progression.
• Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib cycles, or 20 mg per week for patients over 75 years, underweight (BMI below 18.5), with poorly controlled diabetes or with prior intolerance to steroids.

The partner medicines are dosed according to their own SmPCs.

Premedication and Post-Infusion Medicines

• 1–3 hours before every infusion: a corticosteroid (monotherapy: methylprednisolone 100 mg intravenously, reducible to 60 mg after the second infusion; combination therapy: dexamethasone 20 mg, or the regimen’s own dexamethasone dose), an antipyretic (oral paracetamol 650–1,000 mg) and an antihistamine (diphenhydramine 25–50 mg or equivalent).
• After infusions: with monotherapy, an oral corticosteroid (methylprednisolone 20 mg or equivalent) on each of the two following days; with combination therapy, low-dose oral methylprednisolone (20 mg or less) the next day may be considered unless a regimen corticosteroid is given that day.
• Chronic obstructive pulmonary disease: short- and long-acting bronchodilators and inhaled corticosteroids after infusions should be considered; they may be stopped after the first four infusions if no major reactions occur.
• Herpes zoster: antiviral prophylaxis should be considered.

Infusion Rates and Reactions

• The first 16 mg/kg dose is diluted in 1,000 mL and started at 50 mL/hour, increasing by 50 mL/hour every hour to a maximum of 200 mL/hour; it may be split over two days (8 mg/kg in 500 mL each day). The week 2 dose uses 500 mL if there was no reaction the week before, and later infusions may start at 100 mL/hour if the previous infusion caused no reaction. The rate is increased only in the absence of infusion reactions.
• For a reaction of any grade, the infusion is interrupted at once. After grade 1–2 reactions it is resumed at no more than half the rate at which the reaction occurred; after grade 3 reactions a restart at no more than half the rate may be considered. Treatment is stopped permanently after a third grade 3 or higher reaction, or after any grade 4 or anaphylactic reaction.
• Eye symptoms: interrupt the infusion and obtain an immediate ophthalmological assessment before restarting.

Dose Adjustments and Missed Doses

• No dose reduction of daratumumab is recommended; doses may be delayed to allow blood counts to recover.
• A missed dose is given as soon as possible and the schedule adjusted to keep the treatment interval.

Special Populations

• Renal impairment: no formal studies; no dose adjustment needed.
• Hepatic impairment: no formal studies; no dose adjustment needed.
• Elderly: no dose adjustment needed.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Method of Administration

Intravenous infusion after dilution with sodium chloride 9 mg/mL (0.9%) solution for injection.

Subcutaneous Form (1,800 mg Solution for Injection)

The subcutaneous form has its own SmPC. The dose is a fixed 1,800 mg (one 15 mL vial) by subcutaneous injection over about 3 to 5 minutes, whatever the body weight. It must never be given intravenously.

• With lenalidomide and dexamethasone, with pomalidomide and dexamethasone, and as monotherapy (4-week cycles): weekly in weeks 1–8 (8 doses), every 2 weeks in weeks 9–24 (8 doses), then every 4 weeks from week 25 until disease progression.
• With bortezomib, melphalan and prednisone (6-week cycles): weekly in weeks 1–6 (6 doses), every 3 weeks in weeks 7–54 (16 doses), then every 4 weeks from week 55 until disease progression.
• With bortezomib, thalidomide and dexamethasone (transplant-eligible, 4-week cycles): weekly in weeks 1–8 (8 doses) and every 2 weeks in weeks 9–16 (4 doses) before the transplant, then every 2 weeks in weeks 1–8 (4 doses) after it.
• With bortezomib, lenalidomide and dexamethasone: in 3-week cycles for patients not eligible for transplant, weekly in weeks 1–6 (6 doses), every 3 weeks in weeks 7–24 (6 doses), then every 4 weeks from week 25. In 4-week cycles for transplant-eligible patients, weekly in weeks 1–8, every 2 weeks in weeks 9–16, every 2 weeks in weeks 17–24 (the re-start after recovery from the transplant), then every 4 weeks from week 25 until disease progression.
• With bortezomib and dexamethasone (3-week cycles): weekly in weeks 1–9 (9 doses), every 3 weeks in weeks 10–24 (5 doses), then every 4 weeks from week 25 until disease progression.
• Smouldering multiple myeloma (monotherapy) and AL amyloidosis (with bortezomib, cyclophosphamide and dexamethasone): the same 4-week schedule as for lenalidomide and dexamethasone. In smouldering myeloma, treatment continues until disease progression or for a maximum of 3 years; in the AL amyloidosis study it was given until progression or for a maximum of 24 cycles (about 2 years).
• Who gives it: the first four doses are given by a healthcare professional, the first in an environment where resuscitation facilities are available. After training in preparation and injection technique, a patient or caregiver may give the later doses if the healthcare professional judges it appropriate, with medical follow-up as needed.
• Injection: 15 mL into the subcutaneous tissue of the abdomen, about 7.5 cm to the right or left of the navel; no other site has been studied. The sites are rotated, and the injection is never given into red, bruised, tender, hard or scarred skin. If the patient has pain, the injection is paused or slowed, and the rest of the dose may be given at a second site on the opposite side of the abdomen. Other subcutaneous medicines are not injected at the same site.
• Premedication: as for the infusion, a corticosteroid, paracetamol and an antihistamine are given 1–3 hours before every injection and an oral corticosteroid afterwards; oral montelukast 10 mg is recommended on cycle 1 day 1 in smouldering myeloma. Post-injection corticosteroids (not counting those of the background regimen) may be stopped if there are no major reactions after the first three injections. In clinical studies no change of rate or dose was needed to manage injection-related reactions.
• Switching, missed doses and body weight: patients on the intravenous form can switch to the subcutaneous form from the next scheduled dose, so the vial label is checked to make sure the right formulation and dose are given. A missed dose is given as soon as possible and the schedule adjusted. Few patients over 120 kg have been studied with the fixed dose and its efficacy in them has not been established; no dose adjustment for body weight is recommended.

Infusion-Related Reactions

Infusion-related reactions, including anaphylaxis, can be serious or life-threatening, and fatal outcomes have been reported. They occurred in about half of patients in clinical studies, mostly at the first infusion and mostly grade 1–2; 4% of patients had a reaction at more than one infusion. Typical symptoms are nasal congestion, cough, throat irritation, chills, vomiting and nausea. Severe reactions have included bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal and pulmonary oedema, and eye reactions (choroidal effusion, acute myopia, acute angle-closure glaucoma). Patients are monitored throughout every infusion and, after a reaction, until symptoms resolve.

Neutropenia, Thrombocytopenia and Infections

Daratumumab can increase the neutropenia and thrombocytopenia caused by background therapy, so blood counts are monitored and transfusions or growth factors may be used. Serious, life-threatening or fatal infections can occur; patients are watched for infection before and during treatment, and antimicrobial prophylaxis should be considered according to guidelines. Hepatitis B virus reactivation, in some cases fatal, has been reported: all patients are screened for hepatitis B before treatment, those with positive serology are monitored during treatment and for at least 6 months afterwards, and daratumumab is suspended if reactivation occurs.

Blood Transfusions

Daratumumab can make the indirect Coombs test positive for up to 6 months after the last infusion and may mask antibodies to minor antigens; ABO and RhD typing are not affected. Patients should be typed and screened before starting treatment (phenotyping may be considered; genotyping is not affected). Blood transfusion centres should be told about the interference before a planned transfusion; in an emergency, non-cross-matched ABO/RhD-compatible red cells can be given according to local practice.

Myeloma Response Assessment

Daratumumab is detected by serum protein electrophoresis and immunofixation, which can affect the assessment of complete response and of disease progression in some patients with IgG kappa myeloma protein. In persistent very good partial response, a validated daratumumab-specific immunofixation assay can help.

Stem Cell Mobilisation

In transplant-eligible patients given daratumumab with bortezomib, thalidomide and dexamethasone, the CD34+ stem cell yield was numerically lower (median 6.3 compared with 8.9 × 10⁶ cells/kg) and more patients needed plerixafor (21.7% compared with 7.9%), but engraftment rates were similar (99.8% and 99.6%).

Traceability

As for all biological medicines, the product name and batch number should be recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for 3 months after it.
• Pregnancy: human data are very limited and animal studies are insufficient. Daratumumab is not recommended in pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is not known whether daratumumab passes into human milk; a decision is made between stopping breastfeeding and stopping treatment.
• Fertility: no data are available.

Sorbitol

Each 5 mL vial contains 273.3 mg and each 20 mL vial 1,093 mg of sorbitol (E420); each 15 mL vial of the solution for injection contains 735.1 mg. Patients with hereditary fructose intolerance must not be given it unless strictly necessary, and a history of fructose-intolerance symptoms is taken before treatment.

Effect on Driving

Daratumumab has no or negligible influence on the ability to drive and use machines, but fatigue has been reported and should be taken into account.

Store unopened vials in a refrigerator at 2–8 °C, in the original package to protect them from light. Do not freeze. The vials are kept in an unbroken cold chain to the pharmacy that prepares the infusion.

The diluted solution should be used immediately. If it is not, it can be kept for no more than 24 hours in a refrigerator (2–8 °C), protected from light, followed by no more than 15 hours, including the infusion time, at room temperature (15–25 °C) and room light. A refrigerated solution should reach room temperature before administration.

The solution for injection is also kept in a refrigerator at 2–8 °C in the original package, protected from light, and is not frozen. Unpunctured vials may be kept at room temperature (up to 30 °C) for a single period of up to 24 hours; a vial that has been taken out of the refrigerator must not be put back. Once drawn into a syringe, the solution is chemically and physically stable for 24 hours at 2–8 °C, followed by no more than 12 hours at 15–25 °C in ambient light. From a microbiological point of view it should be used immediately; otherwise in-use storage times and conditions are the user’s responsibility.

Unopened vials: 3 years (concentrate and solution for injection). Do not use after the expiry date on the carton.

Prescription only (Rx). Darzalex infusions must be given by a healthcare professional in an environment with resuscitation facilities, and the first four subcutaneous doses by a healthcare professional too, so it is supplied to the hospital or clinic that administers it, in a refrigerated cold chain (2–8 °C). The infusion concentrate is packed as single 5 mL or 20 mL vials and as an initiation pack of 11 vials (six 5 mL and five 20 mL vials).