1. NAME OF THE MEDICINAL PRODUCT

DARZALEX 1800 mg solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 15 mL vial of solution for injection contains 1800 mg of daratumumab (120 mg of daratumumab per mL).

Daratumumab is a human IgG1κ anti-CD38 monoclonal antibody, produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology.

Excipients with known effects

Each 15 mL vial of solution for injection contains 735.1 mg of sorbitol (E420).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

The solution may vary from clear to opalescent and from colourless to yellow, with a pH of 5.6 and an osmolality of 343-395 mOsm/kg.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Multiple myeloma

DARZALEX is indicated:

• in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant.
• in combination with bortezomib, lenalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma.
• in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.
• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
• in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy containing a proteasome inhibitor and lenalidomide and who were refractory to lenalidomide, or who have received at least two prior lines of therapy containing lenalidomide and a proteasome inhibitor and who have demonstrated disease progression during or after the last therapy (see section 5.1).
• as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma whose prior therapies included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression during the last therapy.

Indolent or smouldering multiple myeloma

DARZALEX as monotherapy is indicated for the treatment of adult patients with indolent or smouldering multiple myeloma at high risk of developing multiple myeloma (see section 5.1).

Light chain (AL) amyloidosis

DARZALEX is indicated in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic AL amyloidosis.

4.2 Posology and method of administration

The subcutaneous formulation of DARZALEX is not intended for intravenous administration and must be administered exclusively by subcutaneous injection, using the indicated doses.

DARZALEX must be administered by a healthcare professional, and the first dose must be administered in a setting where resuscitation facilities are available.

It is important to check the vial labels to ensure that the patient receives the correct formulation (intravenous or subcutaneous) and the correct dose as prescribed.

In patients currently receiving the intravenous formulation of daratumumab, DARZALEX solution for subcutaneous injection may be used as an alternative to the intravenous daratumumab formulation starting from the next scheduled dose.

Medicinal products must be administered before and after the injection to reduce the risk of infusion-related reactions (IRRs) with daratumumab. See below "Recommended concomitant medicinal products" and section 4.4.

Posology

Multiple myeloma

Dosing schedule in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone (4-week cycle regimen) and as monotherapy:

The recommended dose of DARZALEX solution for subcutaneous injection is 1800 mg administered over approximately 3-5 minutes according to the following dosing schedule reported in Table 1.

^a The first dose of the every-2-week dosing schedule is administered at week 9.
^b The first dose of the every-4-week dosing schedule is administered at week 25.

Dexamethasone must be administered at a dose of 40 mg/week (or a reduced dose of 20 mg/week for patients aged > 75 years).

For the dose and schedule of the medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle regimens)

The recommended dose of DARZALEX solution for subcutaneous injection is 1800 mg administered over approximately 3-5 minutes according to the following dosing schedule reported in Table 2.

^a The first dose of the every-3-week dosing schedule is administered at week 7.
^b The first dose of the every-4-week dosing schedule is administered at week 55.

Bortezomib is administered twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once-weekly administrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the dose and schedule of VMP administered with DARZALEX solution for subcutaneous injection, see section 5.1.

Dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for the treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT)

The recommended dose of DARZALEX solution for subcutaneous injection is 1800 mg administered over approximately 3-5 minutes according to the following dosing schedule reported in Table 3.

^a The first dose of the every-2-week dosing schedule is administered at week 9.
^b The first dose of the every-2-week dosing schedule is administered at week 1 upon re-initiation of treatment following autologous stem cell transplant.

Dexamethasone must be administered at a dose of 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2, and at a dose of 40 mg on days 1-2 and 20 mg on the subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4. Dexamethasone 20 mg must be administered on days 1, 2, 8, 9, 15, 16 of cycles 5 and 6.

For the dose and schedule of the medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle regimens) for the treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT)

The recommended dose of DARZALEX solution for subcutaneous injection is 1800 mg administered over approximately 3-5 minutes according to the following dosing schedule reported in Table 4.

^a The first dose of the every-2-week dosing schedule is administered at week 9.
^b Week 17 corresponds to the resumption of treatment following recovery from ASCT.
^c DARZALEX may be discontinued in patients who have achieved MRD negativity maintained for 12 months and have undergone maintenance treatment for at least 24 months.

Dexamethasone must be administered at a dose of 40 mg on days 1-4 and on days 9-12 of each 28-day cycle during induction and consolidation (cycles 1-6).

For the dose and schedule of the medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (3-week cycle regimens) for the treatment of newly diagnosed patients not eligible for autologous stem cell transplant (ASCT)

The recommended dose of DARZALEX solution for subcutaneous injection is 1800 mg administered over approximately 3-5 minutes according to the following dosing schedule reported in Table 5.

^a The first dose of the every-3-week dosing schedule is administered at week 7.
^b The first dose of the every-4-week dosing schedule is administered at week 25.

Dexamethasone must be administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each 21-day cycle of cycles 1-8. For patients aged > 75 years or underweight (BMI < 18.5), dexamethasone may be administered at a dose of 20 mg on days 1, 4, 8 and 11.

For the dose and schedule of the medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib and dexamethasone (3-week cycle regimen)

The recommended dose of DARZALEX solution for subcutaneous injection is 1800 mg administered over approximately 3-5 minutes according to the following dosing schedule reported in Table 6.

^a The first dose of the every-3-week dosing schedule is administered at week 10.
^b The first dose of the every-4-week dosing schedule is administered at week 25.

Dexamethasone must be administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 cycles of treatment with bortezomib, or at the reduced dose of 20 mg/week in patients aged > 75 years, underweight (BMI < 18.5), with poorly controlled diabetes mellitus or with prior intolerance to steroid therapy.

For the dose and schedule of the medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Indolent or smouldering multiple myeloma

Dosing schedule for monotherapy (4-week cycle dosing regimen)

The recommended dose is 1 800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the dosing schedule reported below in Table 7.

^a The first dose of the every-2-week dosing schedule is administered at week 9.
^b The first dose of the every-4-week dosing schedule is administered at week 25.

AL amyloidosis

Dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle regimens)

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administered over approximately 3-5 minutes according to the dosing schedule reported in Table 8.

^a In the clinical study, DARZALEX was administered until disease progression or for a maximum of 24 cycles (~2 years) from the first dose of study treatment.
^b The first dose of the every-2-week dosing schedule is administered at week 9.
^c The first dose of the every-4-week dosing schedule is administered at week 25.

For the dose and schedule of the medicinal products administered with DARZALEX solution for subcutaneous injection, see section 5.1 and the corresponding summary of product characteristics.

Missed doses

If a planned dose of DARZALEX is not administered, it must be administered as soon as possible and the dosing schedule must be adjusted accordingly, maintaining the indicated interval between administrations.

Dose modifications

No dose reductions of DARZALEX are recommended. A delay in dose administration may be necessary to allow recovery of blood cell counts in the event of hematologic toxicity (see section 4.4). For information concerning medicinal products administered in combination with DARZALEX, see the corresponding Summary of Product Characteristics.

In clinical studies, no modifications of the rate or dose of DARZALEX solution for subcutaneous injection were necessary to manage IRRs.

Recommended concomitant medicinal products

Pre-injection medicinal products

In order to reduce the risk of IRRs, pre-injection medicinal products (oral or intravenous) must be administered to all patients 1-3 hours before each administration of DARZALEX solution for subcutaneous injection as follows:

• Corticosteroids (long-acting or intermediate-acting)
  –  Monotherapy:
  Methylprednisolone 100 mg (or equivalent). After the second injection, the corticosteroid dose may be reduced to methylprednisolone 60 mg.
  –  Combination therapy:
  Dexamethasone 20 mg (or equivalent), administered before each administration of DARZALEX solution for subcutaneous injection. When dexamethasone is the regimen-specific backbone corticosteroid, the therapeutic dose of dexamethasone will instead serve as the pre-injection medicinal product on the days on which DARZALEX is administered (see section 5.1).
  Additional regimen-specific backbone corticosteroids (e.g. prednisone) must not be taken on the days of DARZALEX administration if patients have received dexamethasone (or equivalent) as the pre-injection medicinal product.
• Antipyretics (paracetamol 650-1000 mg).
• Antihistamine (diphenhydramine 25-50 mg or equivalent, oral or intravenous).
• In patients with indolent or smouldering multiple myeloma, the administration of a leukotriene inhibitor (montelukast 10 mg or equivalent, orally) is recommended on day 1 of cycle 1.

Post-injection medicinal products

To reduce the risk of delayed IRRs, post-injection medicinal products must be administered as follows:

–  Monotherapy:
Oral corticosteroid (methylprednisolone 20 mg or an equivalent dose of an intermediate-acting or long-acting corticosteroid, in accordance with local standards) must be administered on each of the two days following all injections (starting the day after the injection).

–  Combination therapy:
Consider the administration of low-dose methylprednisolone (≤20 mg) or equivalent the day after the DARZALEX injection. However, if a regimen-specific backbone corticosteroid (e.g., dexamethasone, prednisone) is administered the day after the DARZALEX injection, additional post-injection medicinal products may not be needed (see section 5.1).

If the patient does not experience major IRRs after the first three injections, post-injection corticosteroids (excluding the backbone-corticosteroid regimen) may be discontinued.

In addition, for patients with a history of chronic obstructive pulmonary disease, the use of post-injection medicinal products including short-acting and long-acting bronchodilators and inhaled corticosteroids should be considered. After the first four injections, if the patient does not experience major IRRs, these inhaled post-injection medicinal products may be discontinued at the physician's discretion.

Prophylaxis of Herpes zoster virus reactivation

Antiviral prophylaxis must be carried out for the prevention of herpes zoster virus reactivation.

Special populations

Renal impairment

No formal studies with daratumumab have been conducted in patients with renal impairment. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with renal impairment (see section 5.2).

Hepatic impairment

No formal studies with daratumumab have been conducted in patients with hepatic impairment.

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

Elderly patients

No dose adjustments are necessary (see section 5.2).

Pediatric population

The safety and efficacy of DARZALEX in children below 18 years of age have not been established.

No data are available in this population.

Body weight (> 120 kg)

A limited number of patients with body weight >120 kg has been studied using a fixed dose (1800 mg) of DARZALEX solution for subcutaneous injection, and efficacy in these patients has not been established. Currently, no dose adjustment based on body weight can be recommended (see sections 4.4. and 5.2).

Method of administration

The subcutaneous formulation of DARZALEX is not intended for intravenous administration and must be administered exclusively by subcutaneous injection, using the indicated doses. Use the appropriate technique to withdraw DARZALEX from the vial. To reduce the incidence of stopper perforation, avoid using large-diameter or blunt-tipped needles for transfer, and avoid multiple perforations of the stopper. For special precautions before administration, see section 6.6.

To avoid needle obstructions, attach the hypodermic injection needle or the subcutaneous infusion set to the syringe immediately before the injection.

Inject 15 mL of DARZALEX solution for subcutaneous injection into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel, over approximately 3-5 minutes. Do not inject DARZALEX solution for subcutaneous injection at other sites, as no data are currently available.

Injection sites must be rotated for subsequent injections.

DARZALEX solution for subcutaneous injection must never be injected into areas where the skin shows redness, bruising, tenderness or hardening, or into areas where scars are present.

Pause or slow down the administration rate if the patient complains of pain. If the pain is not relieved by slowing the injection, a second injection site may be chosen on the opposite side of the abdomen to administer the remaining dose.

During treatment with DARZALEX solution for subcutaneous injection, do not administer other medicinal products for subcutaneous use at the same site used for DARZALEX.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product must be clearly recorded.

Infusion-related reactions

DARZALEX solution for subcutaneous injection can cause severe and/or serious IRRs, including anaphylactic reactions. In clinical studies, approximately 8.5% (134/1 573) of patients developed an IRR. Most IRRs occurred after the first injection and were grade 1-2. With subsequent injections, IRRs were observed in 1% of patients (see section 4.8).

The median time to onset of IRRs after the DARZALEX injection was 3.3 hours (range 0.08-83 hours). The majority of IRRs occurred on the day of treatment itself. Delayed IRRs were observed in 1% of patients.

Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing, as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension and blurred vision. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle-closure glaucoma) (see section 4.8).

Patients must receive premedication with antihistamines, antipyretics and corticosteroids, and must be monitored and informed regarding IRRs, especially during and after the first and second injection. In patients with indolent or smouldering multiple myeloma, the administration of premedication with leukotriene inhibitors on day 1 of cycle 1 may be considered. If an anaphylactic reaction or a life-threatening reaction (grade 4) occurs, an appropriate emergency procedure must be initiated immediately, and therapy with DARZALEX must be discontinued immediately and permanently (see sections 4.2 and 4.3).

To reduce the risk of delayed IRRs, oral corticosteroids must be administered to all patients after the DARZALEX injection (see section 4.2). In addition, for patients with a clinical history of chronic obstructive pulmonary disease, additional post-injection medicinal products may be necessary to manage respiratory complications. Consider the use of post-injection medicinal products (for example short-acting and long-acting bronchodilators and oral corticosteroids) in patients with chronic obstructive pulmonary disease. If ocular symptoms occur, interrupt the DARZALEX infusion and request an immediate ophthalmologic evaluation before resuming DARZALEX (see section 4.2).

Neutropenia/thrombocytopenia

DARZALEX may increase the neutropenia and thrombocytopenia induced by the backbone therapy (see section 4.8).

During treatment, the complete blood count must be monitored periodically in accordance with the prescribing information reported in the summary of product characteristics of the backbone therapies. Patients with neutropenia must be monitored for signs of infection. A postponement of DARZALEX administration may be necessary to allow recovery of the blood count. In patients with lower body weight treated with the subcutaneous formulation of DARZALEX,

higher rates of neutropenia were observed, which however was not associated with higher rates of serious infections. Dose reduction of DARZALEX is not recommended. Consider supportive therapy with transfusions or growth factors.

Interference with the indirect antiglobulin test (indirect Coombs test)

Daratumumab binds to the CD38 antigen, which is found in small amounts on red blood cells, and may cause a positive indirect Coombs test. Daratumumab-mediated positivity of the indirect Coombs test may persist for up to 6 months after the last administration of daratumumab. It must be recognized that daratumumab bound to red blood cells may mask the detection of antibodies to minor antigens in the patient's serum. The determination of a patient's AB0 blood group and Rh factor is, however, not affected.

Patients must be typed and appropriately screened before starting treatment with daratumumab. Phenotyping, as defined by local practice, should be considered before starting treatment with daratumumab. Red blood cell genotyping is not affected by daratumumab and may be performed at any time.

In the event of a planned transfusion, transfusion centers must be made aware of this interference with the indirect antiglobulin test (see section 4.5). If an emergency transfusion is required, non-cross-matched AB0/RhD-compatible red blood cells may be administered in accordance with local blood bank practice.

Interference with the determination of complete response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected both by serum protein electrophoresis (SPE) and by immunofixation (IFE) assays used for the clinical monitoring of endogenous M-proteins (see section 4.5). This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Hepatitis B virus (HBV) reactivation

Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening must be performed in all patients before starting treatment with DARZALEX.

For patients with evidence of positive HBV serology, monitor the clinical and laboratory signs of HBV reactivation during treatment with DARZALEX and for at least six months after the end of treatment with DARZALEX. Patients must be managed in accordance with current clinical guidelines. Consulting a specialist in liver disease must be considered where indicated by the patients' clinical conditions.

In patients who develop HBV reactivation during treatment with DARZALEX, suspend treatment with DARZALEX and establish appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled must be discussed with physicians experienced in the management of HBV.

Body weight (> 120 kg)

There is a potential reduction in efficacy with DARZALEX solution for subcutaneous injection in patients with body weight >120 kg (see sections 4.2. and 5.2).

Excipients

This medicinal product contains sorbitol (E420); therefore, it must not be administered to patients with hereditary fructose intolerance.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

As an IgG1κ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact daratumumab are unlikely to represent the main elimination routes. As a consequence, variations in drug-metabolizing enzymes are not expected to affect the elimination of daratumumab. Due to its high affinity for a unique epitope on CD38, daratumumab is not anticipated to alter such enzymes.

Clinical pharmacokinetic assessments of the intravenous or subcutaneous formulations of daratumumab in combination with lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib, cyclophosphamide and dexamethasone did not indicate any clinically relevant drug-drug interaction between daratumumab and these small-molecule drugs.

Interference with the indirect antiglobulin test (indirect Coombs test)

Daratumumab binds to the CD38 antigen on red blood cells and interferes with compatibility testing, including antibody screening and cross-matching (see section 4.4). Methods to mitigate daratumumab interference include treating reagent red blood cells with dithiothreitol (DTT) to disrupt daratumumab binding, or other locally validated methods. Since the Kell blood group system is also sensitive to DTT treatment, Kell-negative units must be supplied after ruling out or identifying alloantibodies when DTT-treated red blood cells are used. Alternatively, phenotyping or genotyping may also be considered (see section 4.4).

Interference with serum protein electrophoresis and immunofixation tests

Daratumumab can be detected by the assays used for the monitoring of disease monoclonal immunoglobulins (M-protein), namely serum protein electrophoresis (SPE) and immunofixation (IFE). This can lead to false-positive results in SPE and IFE assays for patients with myeloma characterized by IgG kappa proteins, affecting the initial assessment of complete response according to the International Myeloma Working Group (IMWG) criteria. In patients showing a persistent very good partial response, in whom daratumumab interference is suspected, consider the use of a validated daratumumab-specific IFE assay to distinguish daratumumab from any residual endogenous M-protein in the patient's serum, in order to facilitate the determination of a complete response.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception

Women of childbearing potential must use effective contraceptive measures during the administration of, and for 3 months after, treatment with daratumumab.

Pregnancy

There are no or limited data on the use of daratumumab in pregnant women. Animal studies are insufficient to demonstrate reproductive toxicity (see section 5.3). DARZALEX is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures.

Lactation

It is not known whether daratumumab is excreted in human milk.

A risk to newborns/infants cannot be excluded. The decision to discontinue breast-feeding or to discontinue/abstain from DARZALEX therapy must be made taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No data are available to determine the potential effects of daratumumab on male or female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most frequent adverse reactions of any grade (≥20% of patients) due to daratumumab (intravenous or subcutaneous formulation) administered as monotherapy or in combination were IRRs, fatigue, nausea, diarrhea, constipation, pyrexia, cough, neutropenia, thrombocytopenia, anemia, peripheral edema, peripheral neuropathy, upper respiratory tract infection, musculoskeletal pain and COVID-19. Serious adverse reactions were pneumonia, bronchitis, upper respiratory tract infection, sepsis, pulmonary edema, influenza, pyrexia, dehydration, diarrhea, atrial fibrillation and syncope.

The safety profile of the subcutaneous formulation of DARZALEX was similar to that of the intravenous formulation, with the exception of a lower percentage of IRRs. In the phase III study MMY3012, neutropenia was the only adverse reaction reported with a frequency ≥5% higher with the subcutaneous formulation of DARZALEX than with intravenous daratumumab (grade 3 or 4; 13% and 8%, respectively).

Table of adverse reactions

Table 9 summarizes the adverse reactions observed in patients who received the subcutaneous formulation of DARZALEX or the intravenous formulation of daratumumab.

The data reflect exposure to the subcutaneous formulation of DARZALEX (1800 mg) in 1 187 patients with multiple myeloma (MM). The data include 260 patients from an active-controlled phase III study (study MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy, 149 patients from an active-controlled phase III study (MMY3013) who received the DARZALEX subcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd), 351 patients from an active-controlled phase III study (MMY3014) who received the DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), and 197 patients with newly diagnosed multiple myeloma for whom transplant was not planned as initial therapy or who were not eligible for transplant, from an active-controlled phase III study (MMY3019), who received the DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd). The data also reflect three open-label clinical studies, in two of which patients received DARZALEX solution for subcutaneous injection as monotherapy (N=31, MMY1004 and MMY1008), and one, MMY2040, in which patients received DARZALEX solution for subcutaneous injection in combination with bortezomib, melphalan and prednisone (D-VMP, n=67), lenalidomide and dexamethasone (D-Rd, n=65) or bortezomib, lenalidomide and dexamethasone (D-VRd, n=67). The data reflect

exposure in 193 patients with indolent or smouldering multiple myeloma at high risk of developing multiple myeloma within a randomized phase III study (SMM3001) in which patients received the DARZALEX subcutaneous formulation as monotherapy. The data also reflect exposure in 193 patients with newly diagnosed AL amyloidosis from an active-controlled phase III study (AMY3001), in which patients had received the DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd).

The safety data also reflect exposure to intravenous daratumumab (16 mg/kg) in 2324 patients with multiple myeloma, including 1910 patients who received intravenous daratumumab in combination with backbone regimens and 414 patients who received intravenous daratumumab as monotherapy. Adverse reactions observed after marketing are also included.

Frequency is classified as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1 000, < 1/100), rare (≥ 1/10 000, < 1/1 000) and very rare (< 1/10 000).

^# None of grade 4.
^a Indicates a grouping of terms.
^b Based on post-marketing adverse reactions.
^c Infusion-related reactions also include terms which, in the investigators' judgment, are related to the daratumumab infusion/injection.
^d Injection site reactions also include terms which, in the investigators' judgment, are related to the daratumumab injection.
^e Frequency based only on studies of subcutaneous daratumumab (N=1 573).
^f Frequency based only on studies of intravenous daratumumab (N=2 324).
^g The incidence refers to a subgroup of patients who received at least one dose of treatment on or after 1 February 2020 (start of the COVID-19 pandemic) from studies MMY3003, MMY3006, MMY3008 and MMY3013, and to all patients treated with daratumumab from studies MMY3014, MMY3019 and SMM3001 (N=1 177).
^h Musculoskeletal pain includes back pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain and pain in extremity.
Note: based on 3 897 patients with multiple myeloma and AL amyloidosis treated with intravenous daratumumab or subcutaneous daratumumab.

Description of selected adverse reactions

Infusion-related reactions (IRRs)

In clinical studies (monotherapy and combination treatments, N=1 573) with the subcutaneous formulation of DARZALEX, the incidence of IRRs of any grade was 7.5% with the first

injection of DARZALEX (1 800 mg, week 1), 0.5% with the week 2 injection and 1.3% with subsequent injections. Grade 3 and 4 IRRs were observed in 0.8% and 0.1% of patients, respectively.

Signs and symptoms of IRRs may include respiratory symptoms, such as nasal congestion, cough, throat irritation, allergic rhinitis, wheezing, as well as pyrexia, chest pain, pruritus, chills, vomiting, nausea, blurred vision and hypotension. Serious reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia and ocular adverse reactions (including choroidal effusion, acute myopia and acute angle-closure glaucoma) (see section 4.4).

Injection site reactions (ISRs)

In clinical studies (N=1 573) with the subcutaneous formulation of DARZALEX, the incidence of injection site reactions of any grade was 10.2%. No grade 3 or 4 ISRs were observed. The most common (>1%) ISRs at the injection site were erythema and rash.

Infections

In patients with multiple myeloma treated with daratumumab as monotherapy, the overall incidence of infections was similar between the group treated with the subcutaneous formulation of DARZALEX (52.9%) and the group treated with intravenous daratumumab (50.0%). Grade 3 or 4 infections also occurred with similar frequency with the subcutaneous formulation of DARZALEX (11.7%) and intravenous daratumumab (14.3%). The majority of infections were manageable and rarely led to treatment discontinuation. Pneumonia was the most commonly reported grade 3 or 4 infection in the studies. In active-controlled studies, treatment discontinuations due to infections occurred in 1-4% of patients. Fatal infections were mainly due to pneumonia and sepsis.

In patients with multiple myeloma who received daratumumab in combination therapy, the following were reported:

Grade 3 or 4 infections:
Studies in relapsed/refractory patients: DVd: 21%, Vd: 19%; DRd: 28%; Rd: 23%; DPd: 28%.
Studies in newly diagnosed patients: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; D-VTd: 22%, VTd: 20%.

Grade 5 (fatal) infections:
Studies in relapsed/refractory patients: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%
Studies in newly diagnosed patients: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; D-VTd: 0%, VTd: 0%.

In patients with multiple myeloma who received combination therapy with the DARZALEX subcutaneous formulation, the following infections were reported:

Grade 3 or 4 infections: DPd: 28%, Pd: 23%; D-VRd (transplant-eligible): 35%, VRd (transplant-eligible): 27%; D-VRd (not transplant-eligible): 40%; VRd (not transplant-eligible): 32%
Grade 5 (fatal) infections: DPd: 5%, Pd: 3%; D-VRd (transplant-eligible): 2%, VRd (transplant-eligible): 3%; D-VRd (not transplant-eligible): 8%; VRd (not transplant-eligible): 6%

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

In patients with indolent or smouldering multiple myeloma at high risk of developing multiple myeloma who received the DARZALEX subcutaneous formulation as monotherapy, the following infections were reported:

Grade 3 or 4 infections: DARZALEX subcutaneous formulation: 16%
Grade 5 infections: DARZALEX subcutaneous formulation: 1%

In patients with AL amyloidosis who received combination therapy with the DARZALEX subcutaneous formulation, the following infections were reported:

Grade 3 or 4 infections: D-VCd: 17%, VCd: 10%
Grade 5 infections: D-VCd: 1%, VCd: 1%

Legend: D = daratumumab; VCd = bortezomib-cyclophosphamide-dexamethasone

Hemolysis

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

Cardiac disorders and AL amyloidosis-related cardiomyopathy

Most patients in the AMY3001 study had AL amyloidosis-related cardiomyopathy at baseline (D-VCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of patients treated with D-VCd compared with 10% of patients treated with VCd, while serious cardiac disorders occurred in 16% vs. 13% of patients treated with D-VCd and VCd, respectively. Serious cardiac disorders observed in ≥2% of patients included cardiac failure (D-VCd 6.2% vs. VCd 4.3%), cardiac arrest (D-VCd 3.6% vs. VCd 1.6%) and atrial fibrillation (D-VCd 2.1% vs. VCd 1.1%). All patients treated with D-VCd who suffered serious or fatal cardiac disorders had AL amyloidosis-related cardiomyopathy at baseline. When comparing the frequency of cardiac disorders between the two treatment groups, the longer median duration of treatment in the D-VCd arm compared with the VCd arm (9.6 months vs. 5.3 months, respectively) should be considered. Overall, the exposure-adjusted incidence rates (number of patients with an event per 100 patient-months at risk) of grade 3 or 4 cardiac disorders (1.2 vs. 2.3), cardiac failure (0.5 vs. 0.6), cardiac arrest (0.1 vs. 0.0) and atrial fibrillation (0.2 vs. 0.1) were comparable in the D-VCd arm vs. the VCd arm, respectively.

With a median follow-up of 11.4 months, overall deaths (D-VCd 14% vs. VCd 15%) in the AMY3001 study were mainly due to AL amyloidosis-related cardiomyopathy in both treatment arms.

Other special populations

In the phase III study MMY3007, which compared treatment with D-VMP with treatment with VMP in patients with newly diagnosed multiple myeloma who were not suitable for autologous stem cell transplant, the safety analysis in the subgroups of patients with an ECOG performance status of 2 (D-VMP: n=89, VMP: n=84) was consistent with the total population (see section 5.1).

Elderly patients

Of the 4 553 patients treated with DARZALEX (n=1 615 with the subcutaneous formulation; n=2 938 with the intravenous formulation) at the recommended dose, 38% were aged between 65 and less than 75 years, and 15% were aged over 75 years. Overall, no differences in efficacy were observed based on age. The incidence of severe adverse reactions was higher in older patients than in younger patients. Among patients with relapsed or refractory multiple myeloma (n=1 976), the most common severe adverse reactions that occurred more frequently in the elderly (age ≥ 65 years) were pneumonia and sepsis. Among patients with newly diagnosed multiple myeloma who were not eligible for autologous stem cell transplant (n=777), the most common serious adverse reaction that occurred more frequently in the elderly (age ≥ 75 years) was pneumonia. Among patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplant (n=351), the most common serious adverse reaction that occurred more frequently in the elderly (age ≥ 65 years) was pneumonia. Among patients with newly diagnosed multiple myeloma for whom transplant was not planned as initial therapy or who were not eligible for autologous stem cell transplant (n=197), the most common serious adverse reaction that occurred more frequently in the elderly (age ≥ 65 years) was pneumonia. Among patients with indolent or smouldering multiple myeloma at high risk of developing multiple myeloma (n = 193), the most common serious adverse reaction that occurred more frequently in the elderly (age ≥ 65 years) was pneumonia. Among patients with newly diagnosed AL amyloidosis (n=193), the serious adverse reaction that occurred with greater frequency in elderly patients (age ≥ 65 years) was pneumonia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions that occur after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system listed at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

4.9 Overdose

Symptoms and signs

No cases of overdose were recorded in clinical studies.

Treatment

No specific antidote for daratumumab overdose is known. In the event of overdose, the patient must be monitored for any sign or symptom of adverse reactions, for which appropriate symptomatic treatment must be instituted immediately.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody-drug conjugates, ATC code: L01FC01.

DARZALEX solution for subcutaneous injection contains recombinant human hyaluronidase (rHuPH20). rHuPH20 acts locally and transiently by degrading hyaluronic acid ((HA), a natural glycosaminoglycan present throughout the body) in the extracellular matrix of the subcutaneous space, by cleaving the bond between the two sugars (N-acetylglucosamine and glucuronic acid) that make up HA. In the skin, rHuPH20 has a half-life of less than 30 minutes. Hyaluronic acid levels in the subcutaneous tissue return to normal within 24-48 hours thanks to the rapid biosynthesis of hyaluronic acid.

Mechanism of action

Daratumumab is a human IgG1κ monoclonal antibody (mAb) that binds to the CD38 protein expressed on the cell surface in a number of hematologic malignancies, including clonal plasma cells in multiple myeloma and AL amyloidosis, as well as in other cell types and tissues. The CD38 protein has multiple functions, such as receptor-mediated adhesion, signal transduction activity and enzymatic activity.

Daratumumab has been shown to be a potent inhibitor of the in vivo growth of CD38-expressing tumor cells. Based on in vitro studies, daratumumab may use multiple effector functions, which lead to immune-mediated death of the tumor cell. These studies suggest that, in CD38-expressing tumors, daratumumab can induce tumor cell lysis through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis. A subset of myeloid-derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are reduced by daratumumab-mediated cell lysis. T cells (CD3+, CD4+ and CD8+) are also known to express CD38 depending on their stage of development and level of activation. During treatment with daratumumab, significant increases in the absolute counts of CD4+ and CD8+ T cells and in the percentage of lymphocytes were observed in peripheral whole blood and bone marrow. In addition, T-cell receptor DNA sequencing verified that T-cell clonality

was increased with daratumumab treatment, indicating immunomodulatory effects that may contribute to the clinical response.

Daratumumab induces apoptosis in vitro after Fc-mediated cross-linking. In addition, daratumumab modulates the enzymatic activity of CD38, inhibiting the cyclase activity of the enzyme and stimulating the hydrolase activity. The clinical significance of these in vitro effects, and the implications for tumor growth, are not yet well understood.

Pharmacodynamic effects

Natural Killer (NK) cell and T-cell counts

NK cells are known to express high levels of CD38 and are susceptible to daratumumab-mediated cell lysis. During treatment with daratumumab, decreases in the absolute counts and percentages of total NK cells (CD16+CD56+) and activated NK cells (CD16+CD56^dim) were observed in peripheral whole blood and bone marrow. However, baseline NK cell levels showed no association with clinical response.

Immunogenicity

In patients with multiple myeloma, including indolent or smouldering multiple myeloma at high risk of developing multiple myeloma, and AL amyloidosis treated with subcutaneous daratumumab in clinical studies as monotherapy and combination therapy, less than 1% of patients developed treatment-emergent anti-daratumumab antibodies, and 8 patients tested positive for neutralizing antibodies.

In patients with multiple myeloma, including indolent or smouldering multiple myeloma at high risk of developing multiple myeloma, and AL amyloidosis, the incidence of treatment-emergent anti-rHuPH20 antibodies was 8.9% (133/1 491) in patients who had received the subcutaneous formulation of DARZALEX as monotherapy or in combination therapy, and 1 patient tested positive for neutralizing antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. The clinical relevance of the development of anti-daratumumab or anti-rHuPH20 antibodies after treatment with the subcutaneous formulation of DARZALEX is unknown.

Clinical experience with DARZALEX solution for subcutaneous injection (subcutaneous formulation)

Monotherapy - relapsed/refractory multiple myeloma

MMY3012, a phase III, randomized, open-label, non-inferiority study, compared the efficacy and safety of treatment with DARZALEX solution for subcutaneous injection (1800 mg) versus intravenous daratumumab (16 mg/kg) in patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who were double-refractory to a PI and an IMiD. Treatment continued until unacceptable toxicity or disease progression.

In total, 522 patients were randomized: 263 to the DARZALEX subcutaneous formulation arm and 259 to the intravenous daratumumab arm. Baseline demographic and disease characteristics were similar between the two treatment groups. The median age of the patients was 67 years (range: 33-92 years), 55% were male and 78% were Caucasian. The median weight of the patients was 73 kg (range: 29-138 kg). Patients had received a median of 4 prior lines of therapy. In total, 51% of patients had previously undergone an autologous stem cell transplant (ASCT), 100% of patients had previously been treated with both one or more PIs and one or more IMiDs, and the majority of patients were refractory to a prior systemic therapy, including both the PI and the IMiD (49%).

The study met the co-primary endpoints of overall response rate (ORR) according to the IMWG response criteria (Table 10) and maximum pre-dose C_trough on day 1 of cycle 3 (see section 5.2).

^a Based on the intent-to-treat population.
^b p-value <0.0001 based on the Farrington-Manning test for the non-inferiority hypothesis.
^c Based on the safety population. P-value <0.0001 based on the Cochran-Mantel-Haenszel chi-square test.

After a median follow-up of 29.3 months, median OS was 28.2 months (95% CI: 22.8; NE) in the DARZALEX subcutaneous formulation arm and 25.6 months (95% CI: 22.1; NE) in the intravenous daratumumab arm.

The safety and tolerability results, including patients with lower weight, were consistent with the known safety profile of the subcutaneous formulation of DARZALEX and intravenous daratumumab.

The results of the modified CTSQ instrument, a patient-reported outcomes questionnaire that assesses patient satisfaction with their therapy, indicated that patients treated with the subcutaneous formulation of DARZALEX showed greater satisfaction with their therapy than patients treated with intravenous daratumumab. However, open-label studies are subject to bias.

Combination therapies in multiple myeloma

Combination therapy with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma eligible for autologous stem cell transplant (ASCT)

Study MMY3014 was a phase III, open-label, randomized, active-controlled study that compared induction and consolidation treatment with the subcutaneous formulation of DARZALEX (1800 mg) in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), followed by maintenance with DARZALEX in combination with lenalidomide, versus treatment with bortezomib, lenalidomide and dexamethasone (VRd), followed by maintenance with lenalidomide until documented disease progression or unacceptable toxicity, in patients aged 70 years or younger with newly diagnosed multiple myeloma eligible for ASCT. Before treatment, a short emergency course of corticosteroids was allowed (equivalent to 40 mg/day of dexamethasone for a maximum of 4 days). Patients received the subcutaneous formulation of DARZALEX (1800 mg) administered by subcutaneous injection once weekly (days 1, 8, 15 and 22) for cycles 1-2, followed by once every two weeks (days 1 and 15) for cycles 3-6. For maintenance (cycles 7 onwards), patients received the subcutaneous formulation of DARZALEX (1800 mg) once every 4 weeks. Patients who achieved MRD negativity maintained for 12 months and who had been treated in the maintenance phase for at least 24 months discontinued treatment with the subcutaneous formulation of DARZALEX (1800 mg). Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg/m² of body surface area twice weekly for two weeks (days 1, 4, 8 and 11) in repeated 28-day (4-week) cycles (cycles 1-6). Lenalidomide was administered orally at 25 mg per day on

days 1 to 21 during cycles 1-6. For maintenance (cycles 7 onwards), patients received 10 mg of lenalidomide per day on days 1-28 (continuously) of each cycle until documented disease progression or unacceptable toxicity. Dexamethasone (oral or intravenous) was administered at a dose of 40 mg on days 1-4 and days 9-12 of cycles 1-6. On the days of infusion of the subcutaneous formulation of DARZALEX (1800 mg), the dexamethasone dose was administered orally or intravenously as pre-injection medication. Dose adjustments of bortezomib, lenalidomide and dexamethasone were made according to the information reported in the summary of product characteristics.

A total of 709 patients were randomized: 355 to the D-VRd arm and 354 to the VRd arm. Baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 60 years (range: 31 to 70 years). The majority of patients were male (59%), 64% had an ECOG performance status of 0, 31% had an ECOG performance status of 1 and 5% had an ECOG performance status of 2. In addition, 51% had ISS stage I disease, 34% had ISS stage II disease, 15% had ISS stage III disease, 75% had standard-risk cytogenetics, 22% had high-risk cytogenetics (del17p, t[4;14], t[14;16]) and 3% had indeterminate-risk cytogenetics.

After a median follow-up of 47.5 months, the primary analysis of PFS in the MMY3014 study demonstrated an improvement in PFS in the D-VRd arm compared with the VRd arm (HR = 0.42; 95% CI: 0.30; 0.59; p <0.0001). Median PFS was not reached in either arm.

Further efficacy results obtained in the MMY3014 study are presented in Table 11 below.

D-VRd=daratumumab-bortezomib-lenalidomide-dexamethasone; VRd=bortezomib-lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval
^a Based on the intent-to-treat population
^b P-value based on the Cochran Mantel-Haenszel chi-square test
^c Patients who achieved both MRD negativity (10^-5 threshold) and CR or better
^d A Mantel-Haenszel estimate of the common odds ratio for stratified tables was used

Combination therapy with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma for whom autologous stem cell transplant (ASCT) is not planned as initial therapy or who are not eligible for autologous stem cell transplant (ASCT)

Study MMY3019 was a phase III, open-label, randomized, active-controlled study that compared treatment with the subcutaneous formulation of DARZALEX (1800 mg) in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) versus treatment with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma for whom autologous stem cell transplant (ASCT) had not been planned as initial therapy or who were not eligible for ASCT. Before treatment, a short emergency course of corticosteroids was allowed (equivalent to 40 mg/day of dexamethasone for a maximum of 4 days). Patients received the subcutaneous formulation of DARZALEX (1800 mg) administered by subcutaneous injection once weekly (days 1, 8 and 15) for cycles 1-2, followed by once every 3 weeks for cycles 3-8 and once every four weeks from cycle 9 onwards until documented disease progression or unacceptable toxicity. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² of body surface area twice weekly (days 1, 4, 8 and 11) in repeated 21-day (3-week) cycles (cycles 1-8). Lenalidomide was administered orally at 25 mg per day on days 1 to 14 during cycles 1-8 and on days 1-21 during cycle 9 and beyond. Dexamethasone was administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each of the 21-day (3-week) cycles 1-8, and on days 1, 8, 15 and 22 of each of the 28-day (4-week) cycles from cycle 9 onwards. On the days of injection of the subcutaneous formulation of DARZALEX (1800 mg), the dexamethasone dose was administered orally or intravenously as pre-injection medication. Dose adjustments of bortezomib, lenalidomide and dexamethasone were made according to the summary of product characteristics.

A total of 395 patients were randomized: 197 to the D-VRd arm and 198 to the VRd arm. Baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 70 years (range: 31 to 80 years). 50% of patients were male, 39% had an ECOG performance status of 0, 51% had an ECOG performance status of 1

and 9% had an ECOG performance status of 2. 18% were under 70 years of age and not eligible for transplant, while 27% were under 70 years of age and had deferred transplant. In addition, 34% had ISS stage I disease, 38% had ISS stage II disease, 28% had ISS stage III disease, 75% had standard cytogenetic risk, 13% had high cytogenetic risk (del17p, t[4;14], t[14;16]) and 11% had indeterminate cytogenetic risk.

After a median follow-up of 22.3 months, the primary MRD analysis in the MMY3019 study demonstrated an improvement in the overall MRD negativity rate (by NGS at or below 10^-5) for patients who achieved a CR or better response in the D-VRd arm compared with the VRd arm. The overall MRD negativity rates were 53.3% (95% CI: 46.1; 60.4) in the D-VRd arm and 35.4% (95% CI: 28.7; 42.4) in the VRd arm (odds ratio [D-VRd versus VRd] 2.07 with 95% CI: 1.38; 3.10; p=0.0004).

At the time of the primary MRD analysis, an improvement in the overall rate of CR or better response was observed in the D-VRd arm compared with the VRd arm. The overall rates of CR or better were 76.6% (95% CI: 70.1; 82.4) in the D-VRd arm and 59.1% (95% CI: 51.9; 66.0) in the VRd arm (odds ratio [D-VRd versus VRd] 2.31 with 95% CI: 1.48; 3.60; p=0.0002).

After a median follow-up of 39 months, an interim analysis of PFS in the MMY3019 study demonstrated an improvement in PFS in the D-VRd arm compared with the VRd arm (HR = 0.61; 95% CI: 0.42; 0.90; p=0.0104). Median PFS was not reached in either arm. With more mature data at the final PFS analysis, the treatment effect for PFS was improved, with a hazard ratio of 0.57 (95% CI: 0.41; 0.79). Median PFS was not reached in the D-VRd arm and was 52.6 months in the VRd arm.

At the time of the interim PFS analysis, an improvement in the rate of sustained MRD negativity at 1 year (by NGS at or below 10^-5) was observed for patients who

achieved CR or a better response in the D-VRd arm compared with the VRd arm. Sustained MRD negativity rates were 42.6% (95% CI: 35.6; 49.9) in the D-VRd arm and 25.3% (95% CI: 19.4; 31.9) in the VRd arm (odds ratio [D-VRd versus VRd] 2.18 with 95% CI: 1.42; 3.34; p=0.0003).

Further efficacy results obtained in the MMY3019 study are presented in Table 12 below.

D-VRd=daratumumab-bortezomib-lenalidomide-dexamethasone; VRd=bortezomib-lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval
^a Based on the intent-to-treat population, median follow-up of 59 months
^b Patients who achieved both MRD negativity (threshold at or below 10^-5) and CR or a better rate
^c A Mantel-Haenszel estimate of the common odds ratio for stratified tables was used. The stratification factors are: ISS staging (I, II, III), age/transplant eligibility (<70 years not eligible, or age <70 years and transplant refusal, or age ≥70 years) as randomized. An odds ratio >1 indicates an advantage for D-VRd.
^d Sustained MRD negativity is defined as MRD negative and confirmed by at least a 1-year interval without MRD positivity in the intervening period.

Combination therapies in multiple myeloma

MMY2040 was an open-label study that evaluated the efficacy and safety of the DARZALEX 1800 mg subcutaneous formulation:

• in combination with bortezomib, melphalan and prednisone (D-VMP) in patients with newly diagnosed multiple myeloma (MM) not candidates for transplant. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² of body surface area twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle (cycle 1; 8 doses), followed by once-weekly administrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles (cycles 2-9; 4 doses per cycle). Melphalan 9 mg/m² and prednisone 60 mg/m² were administered orally on days 1 to 4 of the nine 6-week cycles (cycles 1-9). Treatment with the subcutaneous formulation of DARZALEX was continued until disease progression or unacceptable toxicity.
• in combination with lenalidomide and dexamethasone (D-Rd) in patients with relapsed or refractory MM. Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was administered with low-dose dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or with BMI <18.5). Treatment with the subcutaneous formulation of DARZALEX was continued until disease progression or unacceptable toxicity.
• in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) in patients with newly diagnosed MM suitable for transplant. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² of body surface area twice weekly at weeks 1 and 2. Lenalidomide was administered orally at a dose of 25 mg once daily on days 1-14; low-dose dexamethasone was administered at a dose of 40 mg/week in 3-week cycles. The treatment had a total duration of 4 cycles.

In total, 199 patients were enrolled (D-VMP: 67; D-Rd: 65; D-VRd: 67). The efficacy results were determined by a computerized algorithm using the IMWG criteria. The study met its primary endpoint of ORR for D-VMP and D-Rd and the primary endpoint of VGPR or better for D-VRd (see Table 13).

D-VMP = daratumumab-bortezomib-melphalan-prednisone; D-Rd = daratumumab-lenalidomide-dexamethasone; D-VRd = daratumumab-bortezomib-lenalidomide-dexamethasone; daratumumab = subcutaneous formulation of DARZALEX; CI=confidence interval.
^a Based on treated subjects

Combination treatment with pomalidomide and dexamethasone (Pd)

Study MMY3013 was a phase III, randomized, active-controlled, open-label study aimed at comparing treatment with the DARZALEX subcutaneous formulation (1800 mg) in combination with pomalidomide and low-dose dexamethasone (D-Pd) versus treatment with pomalidomide and low-dose dexamethasone (D-Pd) in patients with multiple myeloma who had received at least one prior line of therapy with lenalidomide and a proteasome inhibitor (PI). Pomalidomide (4 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was administered with low-dose dexamethasone 40 mg/week orally or intravenously (or at a reduced dose of 20 mg/week in patients aged >75 years). On the days of administration of the DARZALEX subcutaneous formulation, 20 mg of dexamethasone was administered as the pre-administration medicinal product, and the remaining part was administered the day after the administration. For patients on the reduced dexamethasone dose, the entire 20 mg dose was administered as the pre-administration medicinal product for the DARZALEX subcutaneous formulation. Dose adjustments of pomalidomide and dexamethasone were made according to the information reported in the summary of product characteristics. In both arms, treatment was continued until disease progression or unacceptable toxicity.

A total of 304 patients were randomized: 151 to the D-Pd arm and 153 to the Pd arm. Patients with documented evidence of disease progression during or after the last treatment regimen were included in the study. Patients with grade ≥ 3 rash during prior therapy were excluded, as per the summary of product characteristics of pomalidomide. Baseline demographic data and disease characteristics were similar between the two treatment groups. The median age of the patients was 67 years (range 35 to 90 years), 18% were ≥ 75 years, 53% were male and 89% were of Caucasian origin. Patients had received a median number of 2 prior lines of therapy. All patients had received prior treatment based on a proteasome inhibitor (PI) and lenalidomide, and 56% of patients had received a prior stem cell transplant (ASCT). Ninety-six percent (96%) of patients had received prior bortezomib-based treatment. Most patients were refractory to lenalidomide (80%), to a PI (48%) or to an immunomodulatory agent and a PI (42%). Eleven percent of patients had received one prior line of therapy; all were refractory to lenalidomide and 32.4% were refractory to lenalidomide and a PI. Efficacy was assessed by progression-free survival (PFS) based on the International Myeloma Working Group (IMWG) criteria.

With a median follow-up of 16.9 months, the primary PFS analysis in the MMY3013 study showed a statistically significant improvement in the D-Pd arm compared with the Pd arm; median PFS was 12.4 months in the D-Pd arm and 6.9 months in the Pd arm (HR [95% CI]: 0.63 [0.47; 0.85]; p-value = 0.0018), representing a 37% reduction in the risk of disease progression or death for patients treated with D-Pd compared with Pd.

A further follow-up analysis of OS was performed after a median follow-up of 39.6 months. At an OS data maturity of 57%, median OS was 34.4 months in the D-Pd arm and 23.7 months in the Pd arm (HR [95% CI]: 0.82 [0.61; 1.11]).

Additional efficacy results from the MMY3013 study are presented in Table 14 below.

D-Pd = daratumumab-pomalidomide-dexamethasone; Pd = pomalidomide-dexamethasone; MRD = minimal residual disease; CI = confidence interval.
^a Based on the intent-to-treat population.
^b P-value based on the Cochran Mantel-Haenszel chi-square test adjusted for stratification factors.
^c The MRD negativity rate is based on the intent-to-treat population and a 10^-5 threshold.
^d P-value from Fisher's exact test.

In subjects who responded to treatment, the median time to response was 1 month (range: 0.9 to 9.1 months) in the D-Pd group and 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had not been reached in the D-Pd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.

Monotherapy - Indolent or smouldering multiple myeloma at high risk of developing multiple myeloma

SMM3001, a phase III, open-label, randomized study, compared the efficacy and safety of treatment with the subcutaneous formulation of DARZALEX (1 800 mg) versus active monitoring in patients with indolent or smouldering multiple myeloma at high risk of developing multiple myeloma. For patients randomized to the treatment arm, the subcutaneous formulation of DARZALEX (1 800 mg) was administered subcutaneously once weekly (days 1, 8, 15 and 22) during cycles 1-2, then every 2 weeks (days 1 and 15) during cycles 3-6, and subsequently every 4 weeks for up to 39 cycles or up to 36 months or until confirmed disease progression.

In total, 390 patients were randomized: 194 to the DARZALEX subcutaneous formulation arm and 196 to the active monitoring arm. Baseline demographic and disease characteristics were similar between the two study arms. The median age of the patients was 64 years (range: 31-86 years); 12% were aged ≥ 75 years; 48% were male; 83% were Caucasian, 8% Asian and 3% African American. 83% had an ECOG performance status of 0 and 17% an ECOG performance status of 1. The median percentage of plasma cells in the bone marrow was 20%, and the median time from the date of the initial diagnosis of indolent or smouldering multiple myeloma to randomization was 0.7 years. 80% of patients had fewer than 3 risk factors associated with progression to multiple myeloma. The risk factors were: serum M-protein ≥ 30 g/L; IgA-type SMM; immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes; ratio of involved to uninvolved serum free light chains (FLC) ≥ 8 and < 100; percentage of clonal bone marrow plasma cells (BMPC) from > 50% to < 60% with measurable disease. To be eligible for enrollment in the SMM3001 study, patients had to have at least one of these risk factors and a BMPC percentage ≥ 10%. 19% of patients had serum M-protein levels ≥ 30 g/L, 25% had IgA-type SMM, 60% showed immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, 72% had a ratio of involved to uninvolved serum FLC ≥ 8 and < 100, and 3% a percentage of clonal BMPC from > 50% to < 60% with measurable disease.

The primary endpoint of the study was PFS assessed by the independent review committee (IRC). The Kaplan-Meier curve for PFS is illustrated in Figure 4, and the efficacy results of the SMM3001 study are presented in Table 15 below.

Legend: CI = confidence interval; NV = not evaluable
^a Based on the intent-to-treat population.
^b A Mantel-Haenszel estimate of the common odds ratio for stratified tables was used.
^c The median follow-up was 65.2 months.
^d P-value based on the log-rank test stratified by the stratification factors.

Combination treatment with bortezomib, cyclophosphamide and dexamethasone in patients with AL amyloidosis

The phase III AMY3001 study, randomized, active-controlled, open-label, compared treatment with the DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib,

cyclophosphamide and dexamethasone (D-VCd) versus treatment with bortezomib, cyclophosphamide and dexamethasone alone (VCd) in patients with newly diagnosed systemic AL amyloidosis. Randomization was stratified by the cardiac staging system for AL amyloidosis, countries that normally offer autologous stem cell transplant (ASCT) for patients with AL amyloidosis, and renal function.

All patients enrolled in the AMY3001 study had newly diagnosed AL amyloidosis with at least one involved organ, measurable hematologic disease, cardiac stage I-IIIA (based on the 2004 European modification of the Mayo cardiac staging) and NYHA classification I to IIIA. Patients with NYHA classification IIIB and IV were excluded.

Bortezomib (SC; 1.3 mg/m² of body surface area), cyclophosphamide (oral or IV; 300 mg/m² of body surface area; maximum dose 500 mg), and dexamethasone (oral or IV; 40 mg or a reduced dose of 20 mg for patients aged >70 years or with body mass index [BMI] <18.5 or affected by hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) were administered weekly on days 1, 8, 15 and 22 of repeated 28-day [4-week] cycles. On the days of DARZALEX administration, 20 mg of the dexamethasone dose was administered as the pre-injection medicinal product, and the remaining part was administered the day after the DARZALEX administration. Bortezomib, cyclophosphamide and dexamethasone were administered for six 28-day [4-week] cycles in both treatment arms, while treatment with DARZALEX was continued until disease progression, start of subsequent therapy, or for a maximum of 24 cycles (~2 years) from the first dose of study treatment. Dose adjustments of bortezomib, cyclophosphamide and dexamethasone were made according to the information reported in the summary of product characteristics.

A total of 388 patients were randomized: 195 to the D-VCd arm and 193 to the VCd arm. Baseline demographic data and disease characteristics were similar between the two treatment groups. Most (79%) patients had lambda free light chain disease. The median age of the patients was 64 years (range: 34 to 87); 47% were aged ≥ 65 years; 58% were male; 76% were Caucasian, 17% Asian and 3% African American; 23% had AL amyloidosis Cardiac Clinical stage I, 40% stage II, 35% stage IIIA and 2% stage IIIB. All patients had one or more involved organs, the median number of involved organs was 2 (range: 1-6), and 66% of patients had 2 or more involved organs. Vital organ involvement was: 71% cardiac, 59% renal and 8% hepatic. Patients with grade 2 peripheral sensory neuropathy or grade 1 painful neuropathy were excluded. The primary efficacy endpoint was the hematologic complete response (HemCR) rate as established by the Independent Review Committee assessment based on international consensus criteria. The AMY3001 study demonstrated an improvement in HemCR in the D-VCd arm compared with the VCd arm. The efficacy results are summarized in Table 16.

D-VCd = daratumumab-bortezomib-cyclophosphamide-dexamethasone; VCd = bortezomib-cyclophosphamide-dexamethasone; CI: confidence interval.
^a All results of the planned analysis after a median follow-up of 11.4 months based on the intent-to-treat population.
^b P-value based on the Cochran Mantel-Haenszel chi-square test.
^c MOD-PFS defined as hematologic progression, deterioration of major organs (cardiac or renal) or death.
^d Nominal p-value from the log-rank test with inverse probability of censoring weighting.

With a median follow-up of 11.4 months, in subjects who had responded to treatment, the median time to HemCR was 60 days (range: 8 to 299 days) in the D-VCd group and 85 days (range 14 to 340 days) in the VCd group. The median time to VGPR or better was 17 days (range: 5 to 336 days) in the D-VCd group and 25 days (range 8 to 171 days) in the VCd group. The median duration of HemCR was not reached in either arm.

At the median follow-up of 61.4 months, the overall HemCR rates were 59.5% (95% CI: 52.2; 66.4) in the D-VCd arm and 19.2% (95% CI: 13.9; 25.4) in the VCd arm (odds ratio [D-VCd versus VCd] 6.03, with 95% CI: 3.80; 9.58).

The results of an analysis of the MOD-PFS endpoint conducted after a median follow-up of 61.4 months demonstrated an improvement in MOD-PFS for patients in the D-VCd arm compared with the VCd arm. The hazard ratio (HR) for MOD-PFS was 0.44 (95% CI: 0.31; 0.63) and the p-value was < 0.0001. Median MOD-PFS was not reached in the D-VCd arm and was 30.2 months in the VCd arm. The MOD-PFS rate at 60 months estimated with the Kaplan-Meier method was 60% (95% CI: 52; 67) in the D-VCd arm and 33% (95% CI: 23; 44) in the VCd arm.

After a median follow-up of 61.4 months, a total of 112 deaths was observed (n = 46 [23.6%] in the D-VCd arm versus n = 66 [34.2%] in the VCd arm). Median OS was not reached in either arm; however, the HR for OS was 0.62 (95% CI: 0.42; 0.90) and the p-value was

0.0121. The OS rate at 60 months was 76% (95% CI: 69; 82) in the D-VCd arm and 65% (95% CI: 57; 71) in the VCd arm.

Clinical experience with daratumumab concentrate for solution for infusion (intravenous formulation)

Newly diagnosed multiple myeloma

Combination treatment with lenalidomide and dexamethasone in patients not suitable for autologous stem cell transplant

Study MMY3008, a phase III, open-label, randomized, active-controlled study, compared treatment with intravenous daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) versus treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was administered together with low-dose oral or intravenous dexamethasone of 40 mg/week (or a reduced dose of 20 mg/week for patients aged > 75 years or with body mass index [BMI] <18.5). On the days of the intravenous daratumumab infusion, the dexamethasone dose was administered as pre-infusion medication. Dose adjustments of lenalidomide and dexamethasone were made according to the summary of product characteristics. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. Baseline demographic data and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of patients aged ≥75 years. Most were White (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 49.5% had an ECOG performance status of

1, and 17% had an ECOG performance status ≥2. 27% had stage I disease according to the International Staging System (ISS), 43% had ISS stage II disease and 29% had ISS stage III disease. Efficacy was assessed as progression-free survival (PFS) according to the International Myeloma Working Group (IMWG) criteria, and as overall survival (OS).

After a median follow-up of 28 months, the primary analysis of progression-free survival (PFS) in the MMY3008 study demonstrated an improvement in the DRd arm compared with the Rd arm; median PFS was not reached in the DRd arm and was 31.9 months in the Rd arm (HR=0.56; 95% CI: 0.43; 0.73; p <0.0001), which corresponds to a 44% reduction in the risk of disease progression or death in patients treated with DRd. The results of an updated PFS analysis conducted after a median follow-up of 64 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 61.9 months in the DRd arm and 34.4 months in the Rd arm (HR=0.55; 95% CI: 0.45; 0.67).

After a median follow-up of 56 months, DRd demonstrated an OS advantage over the Rd arm (HR=0.68; 95% CI: 0.53; 0.86; p=0.0013). The results of an updated OS analysis after a median of 89 months continued to show an improvement in OS for patients in the DRd arm compared with the Rd arm. Median OS was 90.3 months in the DRd arm and 64.1 months in the Rd arm (HR=0.67; 95% CI: 0.55; 0.82).

Further efficacy results obtained in the MMY3008 study are presented in Table 17 below.

DRd = daratumumab-lenalidomide-dexamethasone; Rd = lenalidomide-dexamethasone; MRD = minimal residual disease; CI = confidence interval.
^a Based on the intent-to-treat population
^b p-value based on the Cochran Mantel-Haenszel chi-square test.
^c Based on a 10^-5 threshold.
^d A Mantel-Haenszel estimate of the odds ratio for stratified tables was used. An odds ratio >1 indicates an advantage for DRd.
^e p-value based on Fisher's exact test.

In patients responsive to treatment, the median time to response was 1.05 months (range: 0.2-12.1 months) in the DRd group and 1.05 months (range: 0.3-15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8; not estimable) in the Rd group.

Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients not suitable for autologous stem cell transplant

Study MMY3007, a phase III, open-label, randomized, active-controlled study, compared treatment with intravenous daratumumab 16 mg/kg in combination with bortezomib, melphalan and prednisone (D-VMP) versus VMP treatment in patients with newly diagnosed multiple myeloma. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m² of body surface area twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle (cycle 1; 8 doses), followed by once-weekly administrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles (cycles 2-9; 4 doses per cycle). Melphalan 9 mg/m² and prednisone 60 mg/m² were administered orally on days 1 to 4 of the nine 6-week cycles (cycles 1-9). Treatment with intravenous daratumumab continued until disease progression or unacceptable toxicity.

A total of 706 patients were randomized: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics of the two treatment groups were similar. The median age was 71 years (range: 40-93 years), with 30% of patients aged ≥75 years. The majority of patients were Caucasian (85%), female (54%), 25% had an ECOG performance status of 0, 50% had an ECOG performance status of 1 and 25% had an ECOG performance status of 2. Patients had IgG/IgA/light-chain myeloma in 64%/22%/10% of cases, 19% were ISS stage I, 42% ISS stage II, 38% stage III, and 84% had standard-risk cytogenetics. Efficacy was assessed by PFS, based on the IMWG criteria, and by overall survival (OS).

With a median follow-up of 16.5 months, the primary PFS analysis in the MMY3007 study showed an improvement in the D-VMP arm compared with the VMP arm; median PFS was not reached in the D-VMP arm and was 18.1 months in the VMP arm ([HR]=0.5; 95% CI: 0.38; 0.65; p < 0.0001). The results of an updated PFS analysis after a median follow-up of 40 months continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D-VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34; 0.51; p < 0.0001), corresponding to a 58% reduction in the risk of disease progression or death in patients treated with D-VMP.

After a median follow-up of 40 months, D-VMP demonstrated an OS advantage over the VMP arm (HR=0.60; 95% CI: 0.46; 0.80; p=0.0003), corresponding to a 40% reduction in the risk of death in patients treated in the D-VMP arm. After a median follow-up of 87 months, median OS was 83 months (95% CI: 72.5; NE) in the D-VMP arm and 53.6 months (95% CI: 46.3; 60.9) in the VMP arm.

Further efficacy results in the MMY3007 study are presented in Table 18.

D-VMP=daratumumab-bortezomib-melphalan-prednisone; VMP=bortezomib-melphalan-prednisone; MRD=minimal residual disease; CI=confidence interval.
^a Based on the intent-to-treat population.
^b p-value based on the Cochran Mantel-Haenszel chi-square test.
^c Based on a 10^-5 threshold.
^d A Mantel-Haenszel estimate of the common odds ratio for stratified tables was used. An odds ratio >1 indicates an advantage for D-VMP.
^e p-value based on Fisher's exact test.

In patients responsive to treatment, the median time to response was 0.79 months (range 0.4 to 15.5 months) in the D-VMP group and 0.82 months (range 0.7 to 12.6 months) in the VMP group. The median duration of response was not reached in the D-VMP group and was 21.3 months (range 18.4 months to not estimable) in the VMP group.

An analysis was conducted in the subgroup of patients at least 70 years of age, in patients aged 65-69 years with ECOG performance status 2, or in patients under 65 years of age with significant comorbidities or ECOG performance status 2 (D-VMP: n=273, VMP: n=270). The efficacy results of this subgroup were comparable to those of the overall population. In this subgroup, median PFS was not reached in the D-VMP group and was 17.9 months in the VMP group (HR=0.56; 95% CI: 0.42; 0.75; p<0.0001). The overall response rate was 90% in the D-VMP group and 74% in the VMP group (VGPR rate: 29% in the D-VMP group and 26% in the VMP group; CR: 22% in the D-VMP group and 18% in the VMP group; sCR rate: 20% in the D-VMP group and 7% in the VMP group). The safety results of this subgroup were consistent with those of the overall population. In addition, the safety analysis of the subgroup of patients with ECOG performance status 2 (D-VMP: n=89, VMP: n=84) was also comparable to that of the overall population.

Combination treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients eligible for autologous stem cell transplant (ASCT)

Study MMY3006, a phase III, open-label, randomized, active-controlled study, is composed of 2 Parts. Part 1 compared induction and consolidation treatment with intravenous daratumumab 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) versus bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for autologous stem cell transplant (ASCT). The consolidation phase of treatment began at least 30 days after the autologous transplant, when the patient had recovered sufficiently and engraftment was complete.

In Part 2, subjects who had achieved at least a partial response (PR) at day 100 after the transplant were re-randomized to daratumumab maintenance or observation in a 1:1 ratio. From here on, only the results of Part 1 will be described.

Bortezomib was administered by subcutaneous injection or intravenous injection at a dose of 1.3 mg/m² of body surface area twice weekly for two weeks (days 1, 4, 8 and 11) of repeated 28-day (4-week) induction treatment cycles (cycles 1-4) and two consolidation cycles (cycles 5 and 6) following the autologous stem cell transplant after cycle 4. Thalidomide was administered orally at a dose of 100 mg per day during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at a dose of 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and 2, and at doses of 40 mg on days 1-2 and 20 mg on the subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4. Dexamethasone 20 mg was administered on days 1, 2, 8, 9, 15, 16 of cycles 5 and 6. On the days of the intravenous daratumumab infusion, the dexamethasone dose was administered intravenously as the pre-infusion medicinal product. Dose adjustments of bortezomib, thalidomide and dexamethasone were made according to the summary of product characteristics.

A total of 1085 patients were randomized: 543 to the D-VTd arm and 542 to the VTd arm. Baseline demographic data and disease characteristics were similar between the two treatment groups. The median age was 58 (range: 22-65) years. All patients were aged ≤ 65 years: 43% were in the age group ≥ 60-65 years, 41% were in the age group ≥ 50-60 years and 16% were below 50 years of age. The majority were male (59%), 48% had an ECOG performance status of 0, 42% had an ECOG performance status of 1 and 10% had an ECOG performance status of 2. 40% had ISS stage I disease, 45% had ISS stage II disease and 15% had ISS stage III disease.

Efficacy was assessed as the rate of stringent complete response (sCR) at day 100 after transplant, and as PFS.

D-VTd = daratumumab-bortezomib-thalidomide-dexamethasone; VTd = bortezomib-thalidomide-dexamethasone; MRD = minimal residual disease; CI = confidence interval.
^a Based on the intent-to-treat population.
^b p-value based on the Cochran Mantel-Haenszel chi-square test.
^c Based on a 10^-5 threshold.
^d Regardless of IMWG response.
^e A Mantel-Haenszel estimate of the common odds ratio for stratified tables was used.

With a median follow-up of 18.8 months, following censoring of patients on daratumumab maintenance at the second randomization, at the date of the second randomization, the primary PFS analysis showed an HR = 0.50; 95% CI: 0.34; 0.75; p = 0.0005. The results of an updated PFS analysis with a median follow-up of 44.5 months, following censoring of patients on daratumumab maintenance at the second randomization, showed an HR = 0.43; 95% CI: 0.33; 0.55; p < 0.0001. Median PFS was not reached in the D-VTd arm and was 37.8 months in the VTd arm.

Relapsed/refractory multiple myeloma

Monotherapy:

The clinical efficacy and safety of intravenous daratumumab as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who experienced disease progression on the last therapy, were demonstrated in two open-label studies.

In the MMY2002 study, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kg of intravenous daratumumab until disease progression. The median age of the patients was 63.5 years (range 31 to 84 years), 11% of patients were aged ≥75 years, 49% were male and 79% Caucasian. Patients had received a median of 5 prior lines of therapy. 80% of patients had received a prior autologous stem cell transplant (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, 95% were refractory to both proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), 77% were refractory to alkylating agents, 63% to pomalidomide and 48% to carfilzomib.

The efficacy results of the prespecified interim analysis, based on the assessment of an Independent Review Committee (IRC), are reported in Table 20.

¹ Primary efficacy endpoint (International Myeloma Working Group criteria).
CI=confidence interval; NS=not estimable; MR=minimal response.

The overall response rate (ORR) in the MMY2002 study was similar regardless of the type of previously used anti-myeloma therapy.

In an updated survival analysis with a median follow-up duration of 14.7 months, median OS was 17.5 months (95% CI: 13.7; not estimable).

In the GEN501 study, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kg of intravenous daratumumab until disease progression. The median age of the patients was 64 years (range 44 to 76 years), 64% were male and 76% Caucasian. The patients in the study had received a median of 4 prior lines of therapy. 74% of patients had already received ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). At baseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both PI and IMiD, 60% to alkylating agents, 36% to pomalidomide and 17% to carfilzomib.

The prespecified interim analysis indicated that treatment with daratumumab 16 mg/kg led to an ORR of 36%, with 5% CR and 5% VGPR. The median time to response was 1 month (range: 0.5-3.2). The median duration of response was not reached (95% CI: 5.6 months; not estimable).

In an updated survival analysis with a median follow-up duration of 15.2 months, median OS was not reached (95% CI: 19.9 months; not estimable), with 74% of subjects still alive.

Combination treatment with lenalidomide

Study MMY3003, a phase III, open-label, randomized, active-controlled study, compared treatment with intravenous daratumumab 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) versus treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day [4-week] cycles) was administered with low-dose dexamethasone at 40 mg/week (or a reduced dose of 20 mg/week for patients aged > 75 years or with BMI <18.5). On the days of the intravenous daratumumab infusion, 20 mg of the dexamethasone dose was infused as the pre-infusion medicinal product, while the remaining dose was administered the day after the infusion. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. Baseline demographic data and disease characteristics were similar between the intravenous daratumumab arm and the control arm. The median age of the patients was 65 years (range 34 to 89 years), and 11% of patients were aged ≥75 years. Most patients (86%) had received a

prior PI, 55% of patients had received a prior IMiD, of whom 18% of patients had previously received lenalidomide; and 44% of patients had received both a prior PI and an IMiD. At baseline, 27% of patients were refractory to the last line of treatment. 18% were refractory to a PI only, and 21% were refractory to bortezomib. Patients refractory to lenalidomide were excluded from the study.

With a median follow-up of 13.5 months, the primary PFS analysis in the MMY3003 study demonstrated an improvement in the DRd arm compared with the Rd arm; median PFS was not reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27; 0.52; p <0.0001). The results of an updated PFS analysis after a median follow-up of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 45.0 months in the DRd arm and 17.5 months in the Rd arm (HR=0.44; 95% CI 0.35; 0.54; p<0.0001), corresponding to a 56% reduction in the risk of disease progression or death in patients treated with DRd (see Figure 12).

After a median follow-up of 80 months, DRd showed an OS advantage over the Rd arm (HR=0.73; 95% CI: 0.58; 0.91; p=0.0044). Median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm.

Further efficacy results in the MMY3003 study are presented in Table 21.

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NS=not estimable.
^a p-value derived from the Cochran Mantel-Haenszel chi-square test.
^b Based on the intent-to-treat population at the 10^-5 threshold.
^c A Mantel-Haenszel estimate of the common odds ratio was used. An odds ratio > 1 indicates an advantage for the DRd arm.
^d The p-value is derived from Fisher's exact test.

Combination treatment with bortezomib

Study MMY3004, a phase III, open-label, randomized, active-controlled study, compared treatment with intravenous daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd) versus treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received at least one prior therapy. Bortezomib was administered by subcutaneous injection or intravenous injection at a dose of

1.3 mg/m² of body surface area twice weekly for two weeks (days 1, 4, 8 and 11) of repeated 21-day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of each of the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle), or at a reduced dose of 20 mg/week for patients aged >75 years or with BMI <18.5, poorly controlled diabetes mellitus or prior intolerance to steroid therapy. On the days of the intravenous daratumumab infusion, 20 mg of the dexamethasone dose was administered as the pre-infusion medicinal product. Treatment with intravenous daratumumab continued until disease progression or unacceptable toxicity.

A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. Baseline demographic data and disease characteristics were similar between the intravenous daratumumab arm and the control arm. The median age of the patients was 64 years (range 30 to 88 years) and 12% were aged ≥75 years. Sixty-nine percent (69%) of patients had received a prior PI (66% had received bortezomib) and 76% of patients had received an IMiD (42% had received lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment. Thirty-three percent (33%) of patients were refractory to an IMiD only, and 28% were refractory to lenalidomide. Patients refractory to bortezomib were excluded from the study.

With a median follow-up of 7.4 months, the primary PFS analysis in the MMY3004 study demonstrated an improvement in the DVd arm compared with the Vd arm; median PFS was not reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28; 0.53]; p-value <0.0001). The results of an updated PFS analysis after a median follow-up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31 [0.24; 0.39]; p-value <0.0001), corresponding to a 69% reduction in the risk of disease progression or death in patients treated with DVd compared with Vd (see Figure 14).

After a median follow-up of 73 months, DVd showed an OS advantage over the Vd arm (HR=0.74; 95% CI: 0.59; 0.92; p=0.0075). Median OS was 49.6 months in the DVd arm and 38.5 months in the Vd arm.

Further efficacy results in the MMY3004 study are presented in Table 22.

DVd=daratumumab-bortezomib-dexamethasone; Vd=bortezomib-dexamethasone; MRD=minimal residual disease; CI=confidence interval; NS=not estimable.
^a p-value derived from the Cochran Mantel-Haenszel chi-square test.
^b Based on the intent-to-treat population at the 10^-5 threshold.
^c A Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for the DVd arm.
^d The p-value is derived from Fisher's exact test.

Cardiac electrophysiology

Daratumumab, being a large protein, has a low probability of direct interaction with ion channels. The effect of daratumumab on the QTc interval was evaluated in an open-label study of

83 patients (GEN501 study) with relapsed and refractory multiple myeloma after daratumumab infusions (4 to 24 mg/kg). Linear mixed-effects pharmacokinetic-pharmacodynamic models did not indicate a large increase in the mean QTcF interval (that is, greater than 20 ms) at the daratumumab C_max.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with DARZALEX in all subsets of the pediatric population with multiple myeloma (see section 4.2 for information on pediatric use).

5.2 Pharmacokinetic properties

In patients with multiple myeloma, daratumumab exposure in a monotherapy study after administration of the recommended dose of 1800 mg of the DARZALEX subcutaneous formulation (every week for 8 weeks, every other week for 16 weeks, thereafter once monthly) compared with 16 mg/kg of intravenous daratumumab with the same dosing schedule demonstrated non-inferiority for the co-primary endpoint of maximum C_trough (cycle 3 day 1 pre-dose), with a mean ± SD of 593 ± 306 µg/mL versus 522 ± 226 µg/mL for intravenous daratumumab, with a geometric mean ratio of 107.93% (90% CI: 95.74-121.67).

In the AMY3001 combination study, the maximum C_trough (cycle 3 day 1 pre-dose) in patients with AL amyloidosis was similar to that in patients with multiple myeloma, with a mean ± SD of 597 ± 232 µg/mL following the recommended administration of 1800 mg of the DARZALEX subcutaneous formulation (weekly for 8 weeks, every two weeks for 16 weeks, monthly thereafter).

After the recommended dose of 1800 mg of DARZALEX solution for subcutaneous injection, peak concentrations (C_max) increased 4.8-fold and total exposure (AUC_{0-7 days}) increased 5.4-fold from the first to the last weekly dose (8th dose). The maximum pre-dose (trough) concentrations for DARZALEX solution for subcutaneous injection were typically observed at the end of the weekly dosing regimens for both monotherapy and combination therapy.

In patients with multiple myeloma, the simulated pre-dose (trough) concentrations after 6 weekly doses of 1800 mg of DARZALEX solution for subcutaneous injection in combination therapy were similar to those observed with 1800 mg of DARZALEX solution for subcutaneous injection as monotherapy.

In patients with newly diagnosed multiple myeloma suitable for ASCT, daratumumab exposure in a combination study with bortezomib, lenalidomide and dexamethasone (MMY3014) was similar to that in monotherapy, with a mean maximum C_trough (cycle 3 day 1 pre-dose) mean ± SD of 526 ± 209 µg/mL following the recommended administration of 1800 mg of DARZALEX solution for subcutaneous injection (weekly for 8 weeks, every two weeks for 16 weeks, monthly thereafter).

In patients with newly diagnosed multiple myeloma for whom ASCT had not been planned as initial therapy or who were not eligible for ASCT, daratumumab exposure in a combination study with bortezomib, lenalidomide and dexamethasone (study MMY3019) was similar to that in monotherapy and other combination therapies following a similar dosing schedule, with a mean maximum C_trough (cycle 3 day 1 pre-dose) mean ± SD of 407 ± 183 µg/mL following the recommended administration of 1800 mg of DARZALEX solution for subcutaneous injection (weekly for 6 weeks, every three weeks for 18 weeks, monthly thereafter).

In patients with multiple myeloma, daratumumab exposure in a combination study with pomalidomide and dexamethasone (study MMY3013) was similar to that in monotherapy, with a mean

maximum C_trough (cycle 3 day 1 pre-dose) mean ± SD of 537 ± 277 µg/mL following the recommended administration of 1800 mg of DARZALEX solution for subcutaneous injection (weekly for 8 weeks, every two weeks for 16 weeks, monthly thereafter).

In patients with indolent or smouldering multiple myeloma at high risk of developing multiple myeloma, daratumumab exposure in a monotherapy study (SMM3001) was similar to that observed with monotherapy treatment of multiple myeloma, with mean ± SD values of maximum C_trough (cycle 3 day 1, pre-dose) of 654 ± 243 µg/mL following administration of the recommended dose of 1800 mg of DARZALEX solution for subcutaneous injection (weekly for 8 weeks, every two weeks for 16 weeks, then monthly).

Absorption and distribution

In patients with multiple myeloma, at the recommended dose of 1800 mg, the absolute bioavailability of DARZALEX solution for subcutaneous injection is 69%, with an absorption rate of 0.012 hour^-1 and peak concentrations observed after 70-72 hours (T_max). In patients with AL amyloidosis, at the recommended dose of 1800 mg, the absolute bioavailability was not assessed, the absorption rate constant was 0.77 day^-1 (8.31% CV) and peak concentrations were observed at 3 days.

In patients with multiple myeloma, the model-predicted estimated mean volume of distribution was 5.25 L (36.9% CV) for the central compartment and 3.78 L for the peripheral compartment (V2) with daratumumab as monotherapy, and the model-predicted mean estimate of the volume of distribution for V1 was 4.36 L (28.0% CV) and for V2 was 2.80 L when daratumumab was administered in combination with pomalidomide and dexamethasone. In patients with AL amyloidosis, the model-estimated apparent volume of distribution after subcutaneous administration is 10.8 L (3.1% CV). These results suggest that daratumumab is mainly localized in the vascular system, with limited distribution in extravascular tissue.

Metabolism and elimination

Daratumumab exhibits pharmacokinetics (PK) that are both concentration- and time-dependent, with parallel linear and non-linear (saturable) elimination characteristic of target-mediated clearance. In patients with multiple myeloma, the mean clearance of daratumumab estimated by the population PK model is 4.96 mL/h (58.7% CV) with daratumumab as monotherapy and 4.32 mL/h (43.5% CV) when daratumumab was administered in combination with pomalidomide and dexamethasone. In patients with AL amyloidosis, the apparent clearance after subcutaneous administration is 210 mL/day (4.1% CV). The model-based geometric mean of the half-life associated with linear elimination is 20.4 days (22.4% CV) with daratumumab as monotherapy and 19.7 days (15.3% CV) when daratumumab was administered in combination with pomalidomide and dexamethasone in patients with multiple myeloma, and 27.5 days (74.0% CV) in patients with AL amyloidosis. In monotherapy and combination regimens, steady state is achieved after approximately 5 months into the every-4-week dosing at the recommended dose and schedule (1800 mg; once weekly for 8 weeks, every 2 weeks for 16 weeks, thereafter every 4 weeks).

Population PK analyses were conducted using data from studies in multiple myeloma, including indolent or smouldering multiple myeloma, with DARZALEX solution for subcutaneous injection as monotherapy and in combination therapy. The predicted PK exposures are summarized in Table 23. Daratumumab exposures were similar between patients treated with DARZALEX solution for subcutaneous injection as monotherapy and combination therapies.

The predicted PK exposures for 526 transplant-suitable patients with multiple myeloma who received DARZALEX solution for subcutaneous injection in combination with VRd are summarized in Table 24.

A population PK analysis using data from combination therapy with DARZALEX solution for subcutaneous injection in patients with AL amyloidosis was conducted on

data from 211 patients. At the recommended dose of 1800 mg, the predicted daratumumab concentrations were slightly higher, but generally within the same range, compared with those of patients with multiple myeloma.

Special populations

Age and sex

Based on population PK analyses in patients (33-92 years) treated as monotherapy or with various combination therapies, age showed no statistically significant effect on the PK of daratumumab. No individualization is necessary for patients based on age.

Sex showed a statistically significant effect on PK parameters in patients with multiple myeloma but not in patients with AL amyloidosis. A slightly higher exposure was observed in women than in men, but the difference in exposure is not considered clinically significant. No individualization is necessary for patients based on sex.

Renal impairment

No formal studies of the subcutaneous formulation of DARZALEX have been conducted in patients with renal impairment. Population PK analyses were conducted based on pre-existing renal function data in patients with multiple myeloma receiving the subcutaneous formulation of DARZALEX as monotherapy, or in patients with multiple myeloma or AL amyloidosis treated with the various combination therapies. No clinically important differences in daratumumab exposure were observed between patients with renal impairment and those with normal function.

Hepatic impairment

No formal studies of the subcutaneous formulation of DARZALEX have been conducted in patients with hepatic impairment.

Population PK analyses were conducted in patients with multiple myeloma treated with the subcutaneous formulation of DARZALEX as monotherapy, or in patients with multiple myeloma or AL amyloidosis treated with various combination therapies. No clinically important differences in daratumumab exposure were observed between patients with normal hepatic function and mild hepatic impairment. There were very few patients with moderate and severe hepatic impairment; therefore, no meaningful conclusions can be drawn for these populations.

Ethnicity

Based on population PK analyses in patients who received the subcutaneous formulation of DARZALEX as monotherapy or various combination therapies, daratumumab exposure was similar across ethnicities.

Body weight

The administration of a fixed dose of 1800 mg of the subcutaneous formulation of DARZALEX as monotherapy achieved adequate exposure in all body weight subgroups. In patients

with multiple myeloma, the mean C_trough on cycle 3 day 1 in the lowest body weight subgroup (≤65 kg) was 60% higher, and in the highest weight subgroup (>85 kg) was 12% lower, compared with the subgroup treated with intravenous daratumumab. In some patients with body weight >120 kg, a lower exposure was observed, which could result in lower efficacy. However, this observation is based on a limited number of patients.

In patients with AL amyloidosis, no significant differences in C_trough were observed for the different body weights.

5.3 Preclinical safety data

Toxicology data derive from studies with daratumumab in chimpanzees and with a surrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity tests have been conducted.

No animal studies have been performed to establish the carcinogenic potential of daratumumab.

No animal studies have been conducted to evaluate the potential effects of daratumumab on reproduction and development, or to determine the potential effects on male or female fertility.

No carcinogenicity, genotoxicity or fertility studies have been conducted for recombinant human hyaluronidase. No effects on reproductive tissues and reproductive function, and no systemic exposure to hyaluronidase, were observed in monkeys that received 22 000 U/kg/week subcutaneously (a dose 12 times higher than the human dose) for 39 weeks. Since hyaluronidase is a recombinant form of endogenous human hyaluronidase, no carcinogenicity, mutagenesis or effects on fertility are expected.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Recombinant human hyaluronidase (rHuPH20)
L-histidine
L-histidine hydrochloride monohydrate
L-methionine
Polysorbate 20 (E432)
Sorbitol (E420)
Water for injections

6.2 Incompatibilities

This medicinal product must not be used with other materials except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

3 years.

During the shelf life, the product in unpunctured vials may be stored at room temperature (≤30 ºC) for a single maximum period of 24 hours. After being removed from the refrigerator, the product must not be returned to the refrigerator (see section 6.6).

Prepared syringe

The chemical and physical in-use stability inside the syringe has been demonstrated for 24 hours under refrigerated conditions (2 °C-8 °C), followed by no more than 12 hours at 15 °C-25 °C and at ambient light. From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product must be used immediately. If not used immediately, compliance with the in-use storage conditions and times of the medicinal product is the responsibility of the user.

6.4 Special precautions for storage

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

Store in the original package in order to protect the medicinal product from light.

For the storage conditions of the opened medicinal product, see section 6.3.

6.5 Nature and contents of container

15 mL of solution in a type 1 glass vial with an elastomeric stopper and an aluminium seal with a tear-off cap, containing 1800 mg of daratumumab. Pack of 1 vial.

6.6 Special precautions for disposal and handling

DARZALEX solution for subcutaneous injection is for single use only and is ready for use.

DARZALEX solution for subcutaneous injection must be a clear to opalescent and colourless to yellow solution. Do not use the solution if opaque particles, discolouration or other foreign particles are visible.

DARZALEX solution for subcutaneous injection is compatible with polypropylene or polyethylene syringes; polypropylene, polyethylene or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless-steel transfer and injection needles.

Unopened vial

Remove the vial of DARZALEX solution for subcutaneous injection from the refrigerator where it is stored (2 ºC-8 ºC) and allow it to equilibrate to room temperature (≤30 °C). The unpunctured vial may be stored at ambient temperature and light for a maximum of 24 hours in the original package in order to protect the medicinal product from light. Keep away from direct sunlight. Do not shake.

Prepared syringe

Prepare the administration syringe under controlled and validated aseptic conditions. Withdraw 15 mL from the vial into a syringe using an 18G - 22G transfer needle with a regular bevel to minimize the risk of stopper perforation. Insert the needle into the vial at a 90° angle within the ring of the stopper, and minimize the number of punctures to avoid fragmentation of the stopper. Inspect the contents of the syringe to verify that there are no particles, discolouration or other foreign particles.

After transferring the contents of the vial into the syringe, store DARZALEX solution for subcutaneous injection for a maximum of 24 hours under refrigerated conditions, followed by a maximum of 12 hours at 15 °C-25 °C and at ambient light (see section 6.3). If stored in the refrigerator, allow the solution to reach room temperature before administration.

Any unused medicinal product and waste derived from this medicinal product must be disposed of in accordance with current local regulations.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1101/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 May 2016
Date of latest renewal: 6 January 2022

10. DATE OF REVISION OF THE TEXT

September 2025

More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.