DARZALEX 1800mg 120mg / ml solution for injection medication leaflet

DARZALEX 1800 mg solution for injection

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

Daratumumab is a human monoclonal IgG1κ antibody against CD38 antigen, produced in amammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology.

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.

Solution for injection.

The solution is clear to opalescent, colourless to yellow.

DARZALEX is indicated:

- in combination with lenalidomide and dexamethasone or with bortezomib, melphalan andprednisone for the treatment of adult patients with newly diagnosed multiple myeloma who areineligible for autologous stem cell transplant.

- in combination with bortezomib, lenalidomide and dexamethasone for the treatment of adultpatients with newly diagnosed multiple myeloma.

- in combination with bortezomib, thalidomide and dexamethasone for the treatment of adultpatients with newly diagnosed multiple myeloma who are eligible for autologous stem celltransplant.

- in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, forthe treatment of adult patients with multiple myeloma who have received at least one priortherapy.

- in combination with pomalidomide and dexamethasone for the treatment of adult patients withmultiple myeloma who have received one prior therapy containing a proteasome inhibitor andlenalidomide and were lenalidomide-refractory, or who have received at least two priortherapies that included lenalidomide and a proteasome inhibitor and have demonstrated diseaseprogression on or after the last therapy (see section 5.1).

- as monotherapy for the treatment of adult patients with relapsed and refractory multiplemyeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatoryagent and who have demonstrated disease progression on the last therapy.

Light chain (AL) amyloidosis

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

DARZALEX subcutaneous formulation is not intended for intravenous administration and should begiven by subcutaneous injection only, using the doses specified.

DARZALEX should be administered by a healthcare professional, and the first dose should beadministered in an environment where resuscitation facilities are available.

It is important to check the vial labels to ensure that the appropriate formulation (intravenous orsubcutaneous formulation) and dose is being given to the patient as prescribed.

For patients currently receiving daratumamab intravenous formulation, DARZALEX solution forsubcutaneous injection may be used as an alternative to the intravenous daratumumab formulationstarting at the next scheduled dose.

Pre- and post-injection medicinal products should be administered to reduce the risk ofinfusion-related reactions (IRRs) with daratumumab. See below “Recommended concomitantmedicinal products” and section 4.4.

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

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

Table 1: DARZALEX dosing schedule in combination with lenalidomide and dexamethasone(Rd), pomalidomide and dexamethasone (Pd) (4-week cycle dosing regimen) andmonotherapy

Weeks Schedule

Weeks 1 to 8 weekly (total of 8 doses)

Weeks 9 to 24a every two weeks (total of 8 doses)

Week 25 onwards until disease progressionb every four weeksa First dose of the every-2-week dosing schedule is given at week 9.b First dose of the every-4-week dosing schedule is given at week 25.

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

For dose and schedule of medicinal products administered with DARZALEX solution forsubcutaneous 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 is 1800 mg of DARZALEX solution for subcutaneous injection administeredover approximately 3-5 minutes according to the following dosing schedule in table 2.

Table 2: DARZALEX dosing schedule in combination with bortezomib, melphalan andprednisone ([VMP]; 6-week cycle dosing regimen)

Weeks Schedule

Weeks 1 to 6 weekly (total of 6 doses)

Weeks 7 to 54a every three weeks (total of 16 doses)

Week 55 onwards until disease progressionb every four weeksa First dose of the every-3-week dosing schedule is given at week 7.b First dose of the every-4-week dosing schedule is given at week 55.

Bortezomib is given twice weekly at weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by onceweekly at weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the VMP dose anddosing schedule when administered with DARZALEX solution for subcutaneous injection, seesection 5.1.

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

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

Table 3: DARZALEX dosing schedule in combination with bortezomib, thalidomide anddexamethasone ([VTd]; 4-week cycle dosing regimen)

Treatment phase Weeks Schedule

Induction Weeks 1 to 8 weekly (total of 8 doses)

Weeks 9 to 16a every two weeks (total of 4 doses)

Stop for high dose chemotherapy and ASCT

Consolidation Weeks 1 to 8b every two weeks (total of 4 doses)a First dose of the every-2-week dosing schedule is given at week 9.b First dose of the every-2-week dosing schedule is given at week 1 upon re-initiation of treatment following ASCT.

Dexamethasone should be administered at 40 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1 and2, and at 40 mg on days 1-2 and 20 mg on subsequent dosing days (days 8, 9, 15, 16) of cycles 3-4.

Dexamethasone 20 mg should be administered on days 1, 2, 8, 9, 15, 16 in cycles 5 and 6.

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

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

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

Table 4: DARZALEX dosing schedule in combination with bortezomib, lenalidomide anddexamethasone ([VRd]; 4-week cycle dosing regimen)

Treatment phase Weeks Schedule

Induction Weeks 1 to 8 weekly (total of 8 doses)

Weeks 9 to 16a every two weeks (total of 4 doses)

Stop for high dose chemotherapy and ASCT

Consolidation Weeks 17 to 24b every two weeks (total of 4 doses)

Maintenance Week 25 onwards until disease progressionc every four weeksa First dose of the every-2-week dosing schedule is given at week 9.b Week 17 corresponds to re-initiation of treatment following recovery from ASCT.c DARZALEX can be discontinued for patients who have achieved MRD negativity that is sustained for 12 months andhave been treated on maintenance for at least 24 months.

Dexamethasone should be administered at 40 mg on days 1-4 and days 9-12 of each 28-day cycleduring induction and consolidation (cycles 1-6).

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

Dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (3-week cycleregimens) for treatment of newly diagnosed patients who are ineligible for ASCT

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

Table 5: DARZALEX dosing schedule in combination with bortezomib, lenalidomide anddexamethasone ([VRd]; 3-week cycle dosing regimen)

Weeks Schedule

Weeks 1 to 6 weekly (total of 6 doses)

Weeks 7 to 24a every three weeks (total of 6 doses)

Week 25 onwards until disease progressionb every four weeksa First dose of the every-3-week dosing schedule is given at week 7.b First dose of the every-4-week dosing schedule is given at week 25.

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

For dose and schedule of medicinal products administered with DARZALEX solution forsubcutaneous 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 is 1800 mg of DARZALEX solution for subcutaneous injection administeredover approximately 3-5 minutes according to the following dosing schedule in table 6.

Table 6: DARZALEX dosing schedule in combination with bortezomib and dexamethasone(Vd) (3-week cycle dosing regimen)

Weeks Schedule

Weeks 1 to 9 weekly (total of 9 doses)

Weeks 10 to 24a every three weeks (total of 5 doses)

Week 25 onwards until disease progressionb every four weeksa First dose of the every-3-week dosing schedule is given at week 10.b First dose of the every-4-week dosing schedule is given at week 25.

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

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

AL amyloidosis

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

The recommended dose is 1800 mg of DARZALEX solution for subcutaneous injection administeredover approximately 3-5 minutes according to the following dosing schedule in table 7.

Table 7: DARZALEX dosing schedule for AL amyloidosis in combination with bortezomib,cyclophosphamide and dexamethasone ([VCd]; 4-week cycle dosing regimen)a

Weeks Schedule

Weeks 1 to 8 weekly (total of 8 doses)

Weeks 9 to 24b every two weeks (total of 8 doses)

Week 25 onwards until disease progressionc every four weeksa In the clinical study, DARZALEX was given until disease progression or a maximum of 24 cycles (~ 2 years) from thefirst dose of study treatment.b First dose of the every-2-week dosing schedule is given at week 9.c First dose of the every-4-week dosing schedule is given at week 25.

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

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible andthe dosing schedule should be adjusted accordingly, maintaining the treatment interval.

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recoveryof blood cell counts in the event of haematological toxicity (see section 4.4). For informationconcerning medicinal products given in combination with DARZALEX, see corresponding Summaryof Product Characteristics.

In clinical studies, no modification to rate or dose of DARZALEX solution for subcutaneous injectionwas required to manage IRRs.

Recommended concomitant medicinal products

Pre-injection medicinal product

Pre-injection medicinal products (oral or intravenous) should be administered to reduce the risk of

IRRs to all patients 1-3 hours prior to every administration of DARZALEX solution for subcutaneousinjection as follows:

- Corticosteroid (long-acting or intermediate-acting)

- Monotherapy:

Methylprednisolone 100 mg, or equivalent. Following the second injection, the dose ofcorticosteroid may be reduced to methylprednisolone 60 mg.

- Combination therapy:

Dexamethasone 20 mg (or equivalent), administered prior to every DARZALEX solutionfor subcutaneous injection. When dexamethasone is the background-regimen specificcorticosteroid, the dexamethasone treatment dose will instead serve as pre-injectionmedicinal product on DARZALEX administration days (see section 5.1). Additionalbackground regimen specific corticosteroids (e.g. prednisone) should not be taken on

DARZALEX administration days when patients have received dexamethasone (orequivalent) as a pre-injection medicinal product.

- Antipyretics (paracetamol 650 to 1000 mg).

- Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Post-injection medicinal product

Post-injection medicinal products should be administered to reduce the risk of delayed IRRs asfollows:

- Monotherapy:

Oral corticosteroid (20 mg methylprednisolone or equivalent dose of anintermediate-acting or long-acting corticosteroid in accordance with local standards)should be administered on each of the two days following all injections (beginning theday after the injection).

- Combination therapy:

Consider administering low-dose oral methylprednisolone (≤ 20 mg) or equivalent theday after the DARZALEX injection. However, if a background regimen specificcorticosteroid (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 experiences no major IRRs after the first three injections, post-injection corticosteroids(excluding any background regimen corticosteroids) may be discontinued.

Additionally, for patients with a history of chronic obstructive pulmonary disease, the use ofpost-injection medicinal products including short and long acting bronchodilators, and inhaledcorticosteroids should be considered. Following the first four injections, if the patient experiences nomajor IRRs, these inhaled post-injection medicinal products may be discontinued at the discretion ofthe physician.

Prophylaxis for herpes zoster virus reactivation

Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

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

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

No dose adjustments are necessary for patients with hepatic impairment (see section 5.2).

No dose adjustments are considered necessary (see section 5.2).

The safety and efficacy of DARZALEX in children aged below 18 years of age have not beenestablished.

No data are available.

Body weight (> 120 kg)

Limited number of patients with body weight > 120 kg have been studied using flat-dose (1800 mg)

DARZALEX solution for subcutaneous injection and efficacy in these patients has not beenestablished. No dose adjustment based on body weight can currently be recommended (seesections 4.4 and 5.2).

DARZALEX subcutaneous formulation is not intended for intravenous administration and should begiven by subcutaneous injection only, using the doses specified. See section 6.6 for special precautionsprior to administration.

To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to thesyringe immediately prior to injection.

Inject 15 mL DARZALEX solution for subcutaneous injection into the subcutaneous tissue ofthe abdomen approximately 7.5 cm to the right or left of the navel over approximately3-5 minutes. Do not inject DARZALEX solution for subcutaneous injection at other sites of the bodyas no data are available.

Injection sites should be rotated for successive injections.

DARZALEX solution for subcutaneous injection should never be injected into areas where the skin isred, bruised, tender, hard or areas where there are scars.

Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated byslowing down the injection, a second injection site may be chosen on the opposite side of the abdomento deliver the remainder of the dose.

During treatment with DARZALEX solution for subcutaneous injection, do not administer othermedicinal products for subcutaneous use at the same site as DARZALEX.

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

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

DARZALEX solution for subcutaneous injection can cause severe and/or serious IRRs, includinganaphylactic reactions. In clinical studies, approximately 7% (102/1380) of patients experienced an

IRR. Most IRRs occurred following the first injection and were grade 1-2. IRRs occurring withsubsequent injections were seen in 1% of patients (see section 4.8).

The median time to onset of IRRs following DARZALEX injection was 2.9 hours (range0.08-83 hours). The majority of IRRs occurred on the day of treatment. Delayed IRRs have occurredin 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, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidaleffusion, acute myopia and acute angle closure glaucoma) (see section 4.8).

Patients should be pre-medicated with antihistamines, antipyretics, and corticosteroids as well asmonitored and counselled regarding IRRs, especially during and following the first and secondinjections. If an anaphylactic reaction or life-threatening (grade 4) reactions occur, appropriateemergency care should be initiated immediately. DARZALEX therapy should be discontinuedimmediately and permanently (see sections 4.2 and 4.3).

To reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patientsfollowing DARZALEX injection (see section 4.2). Patients with a history of chronic obstructivepulmonary disease may require additional post-injection medicinal products to manage respiratorycomplications. The use of post-injection medicinal products (e.g. short- and long-actingbronchodilators and inhaled corticosteroids) should be considered for patients with chronic obstructivepulmonary disease. If ocular symptoms occur, interrupt DARZALEX and seek immediateophthalmologic evaluation prior to restarting DARZALEX (see section 4.2).

Neutropenia/thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy (seesection 4.8).

Complete blood cell counts should be monitored periodically during treatment according tomanufacturer’s prescribing information for background therapies. Patients with neutropenia should bemonitored for signs of infection. DARZALEX delay may be required to allow recovery of blood cellcounts. In lower body weight patients receiving DARZALEX subcutaneous formulation, higher ratesof neutropenia were observed; however, this was not associated with higher rates of serious infections.

No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions orgrowth factors.

Interference with indirect antiglobulin test (indirect Coombs test)

Daratumumab binds to CD38 found at low levels on red blood cells (RBCs) and may result in apositive indirect Coombs test. Daratumumab-mediated positive indirect Coombs test may persist forup to 6 months after the last daratumumab administration. It should be recognised that daratumumabbound to RBCs may mask detection of antibodies to minor antigens in the patient’s serum. Thedetermination of a patient’s ABO and Rh blood type are not impacted.

Patients should be typed and screened prior to starting daratumumab treatment. Phenotyping may beconsidered prior to starting daratumumab treatment as per local practice. Red blood cell genotyping isnot impacted by daratumumab and may be performed at any time.

In the event of a planned transfusion blood transfusion centres should be notified of this interferencewith indirect antiglobulin tests (see section 4.5). If an emergency transfusion is required,non-cross-matched ABO/RhD-compatible RBCs can be given per local blood bank practices.

Interference with determination of complete response

Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serumprotein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring ofendogenous M-protein (see section 4.5). This interference can impact the determination of completeresponse 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 should be performed in all patients before initiation of treatment with

DARZALEX.

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

In patients who develop reactivation of HBV while on DARZALEX, suspend treatment with

DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patientswhose HBV reactivation is adequately controlled should be discussed with physicians with expertisein managing HBV.

Body weight (> 120 kg)

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

This medicinal product contains sorbitol (E420). Patients with hereditary fructose intolerance (HFI)should not be given this medicinal product.

This medicinal product also contains less than 1 mmol (23 mg) sodium per dose, that is to sayessentially ‘sodium-free’.

No interaction studies have been performed.

As an IgG1қ monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intactdaratumumab are unlikely to represent major elimination routes. As such, variations indrug-metabolising enzymes are not expected to affect the elimination of daratumumab. Due to thehigh affinity to a unique epitope on CD38, daratumumab is not anticipated to alter drug-metabolisingenzymes.

Clinical pharmacokinetic assessments with daratumumab intravenous or subcutaneous formulationsand lenalidomide, pomalidomide, thalidomide, bortezomib, melphalan, prednisone, carfilzomib,cyclophosphamide and dexamethasone indicated no clinically-relevant drug-drug interaction betweendaratumumab and these small molecule medicinal products.

Interference with indirect antiglobulin test (indirect Coombs test)

Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibodyscreening and cross matching (see section 4.4). Daratumumab interference mitigation methods includetreating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or other locallyvalidated methods. Since the Kell blood group system is also sensitive to DTT treatment,

Kell-negative units should be supplied after ruling out or identifying alloantibodies using DTT-treated

RBCs. Alternatively, phenotyping or genotyping may also be considered (see section 4.4).

Interference with serum protein electrophoresis and immunofixation tests

Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE)assays used for monitoring disease monoclonal immunoglobulins (M protein). This can lead to falsepositive SPE and IFE assay results for patients with IgG kappa myeloma protein impacting initialassessment of complete responses by International Myeloma Working Group (IMWG) criteria. Inpatients with persistent very good partial response, where daratumumab interference is suspected,consider using a validated daratumumab-specific IFE assay to distinguish daratumumab from anyremaining endogenous M protein in the patient’s serum, to facilitate determination of a completeresponse.

Women of child-bearing potential/contraception

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

There are no or limited amount of data from the use of daratumumab in pregnant women. Animalstudies are insufficient with respect to reproductive toxicity (see section 5.3). DARZALEX is notrecommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether daratumumab is excreted in human milk.

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

No data are available to determine potential effects of daratumumab on fertility in males or females(see section 5.3).

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

The most frequent adverse reactions of any grade (≥ 20% patients) with daratumumab (eitherintravenous or subcutaneous formulations) when administered either as monotherapy or combinationtreatment were IRRs, fatigue, nausea, diarrhoea, constipation, pyrexia, cough, neutropenia,thrombocytopenia, anaemia, oedema peripheral, peripheral neuropathy, upper respiratory tractinfection, musculoskeletal pain and COVID-19. Serious adverse reactions were pneumonia, bronchitis,upper respiratory tract infection, sepsis, pulmonary oedema, influenza, pyrexia, dehydration,diarrhoea, atrial fibrillation and syncope.

The safety profile of the DARZALEX subcutaneous formulation was similar to that of intravenousformulation with the exception of a lower rate of IRRs. In the phase III study MMY3012, neutropeniawas the only adverse reaction reported at ≥ 5% higher frequency for DARZALEX subcutaneousformulation compared to intravenous daratumumab (grade 3 or 4: 13% vs 8%, respectively).

Table 8 summarises the adverse reactions that occurred in patients receiving DARZALEXsubcutaneous formulation or intravenous formulation of daratumumab.

The data reflects exposure to DARZALEX subcutaneous formulation (1800 mg) in 1187 patients withmultiple myeloma (MM). The data includes 260 patients from a phase III active-controlled study(MMY3012) who received DARZALEX solution for subcutaneous injection as monotherapy,149 patients from a phase III active-controlled study (MMY3013) who received DARZALEXsubcutaneous formulation in combination with pomalidomide and dexamethasone (D-Pd), 351 patientsfrom a phase III active-controlled study (MMY3014) who received DARZALEX subcutaneousformulation in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), and197 newly diagnosed multiple myeloma patients for whom transplant was not planned as initialtherapy or who were ineligible for transplant from a phase III active-controlled study (MMY3019)who received DARZALEX subcutaneous formulation in combination with bortezomib, lenalidomideand dexamethasone (D-VRd). The data also reflects three open-label, clinical studies in which patientsreceived DARZALEX solution for subcutaneous injection either as monotherapy (N=31, MMY1004and MMY1008) and MMY2040 in which patients received DARZALEX solution for subcutaneousinjection in combination with either bortezomib, melphalan and prednisone (D-VMP, n=67),lenalidomide and dexamethasone (D-Rd, n=65) or bortezomib, lenalidomide and dexamethasone(D-VRd, n=67). Additionally, data reflect exposure to 193 patients with newly diagnosed ALamyloidosis from a phase III active-controlled study (AMY3001) in which patients received

DARZALEX subcutaneous formulation in combination with bortezomib, cyclophosphamide anddexamethasone (D-VCd).

The safety data also reflects exposure to intravenous daratumumab (16 mg/kg) in 2324 patients withmultiple myeloma including 1910 patients who received intravenous daratumumab in combinationwith background regimens and 414 patients who received intravenous daratumumab as monotherapy.

Post-marketing adverse reactions are also included.

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000).

Table 8: Adverse reactions in multiple myeloma and AL amyloidosis patients treatedwith intravenous daratumumab or subcutaneous daratumumab

System organ class Adverse reaction Frequency Incidence (%)

Any grade Grade 3-4

Infections and Upper respiratory tract Very common 45 3infestations infectiona

COVID-19a, g 26 7

Pneumoniaa 19 11

Bronchitisa 14 1

Urinary tract infection Common 8 1

Sepsisa 4 4

Cytomegalovirus infectiona Uncommon < 1 < 1#

Hepatitis B Virus < 1 < 1reactivationa

Blood and lymphatic Neutropeniaa Very common 43 37system disorders Thrombocytopeniaa 32 19

Anaemiaa 27 11

Lymphopeniaa 13 10

Leukopeniaa 11 6

Immune system Hypogammaglobulinemiaa Common 3 < 1#disorders Anaphylactic reactionb Rare - -

Metabolism and Hypokalaemiaa Very common 11 3nutrition disorders Decreased appetite 10 1

Hyperglycaemia Common 7 3

Hypocalcaemia 6 1

Dehydration 2 1#

Psychiatric disorders Insomnia Very common 17 1#

Nervous system Peripheral neuropathy Very common 33 4disorders Headache 10 < 1#

Dizziness Common 9 < 1#

Paraesthesia 9 < 1

Syncope 3 2#

Cardiac disorders Atrial fibrillation Common 4 1

Vascular disorders Hypertensiona Common 9 4

Respiratory, thoracic Cougha Very common 22 < 1#and mediastinal Dyspnoeaa 18 2disorders Pulmonary oedemaa Common 1 < 1

Gastrointestinal Diarrhoea Very common 33 5disorders Constipation 29 1

Nausea 22 1#

Abdominal paina 13 1

Vomiting 13 1#

Pancreatitisa Common 1 1

Skin and Rash Very common 12 1#subcutaneous tissue Pruritus Common 6 < 1#disorders

Musculoskeletal and Musculoskeletal paina Very common 35 3connective tissue Arthralgia 14 1disorders Muscle spasms 12 < 1#

General disorders Fatigue Very common 24 4and administration Oedema peripherala 24 1site conditions Pyrexia 22 1

Asthenia 19 2

Chills Common 8 < 1#

Injection site reactionsd,e 8 0

Injury, poisoning Infusion-related reactionscand procedural Daratumumab Very common 39 5complications intravenousf

Daratumumab Common 7 1subcutaneouse# No grade 4.a Indicates a grouping of terms.b Based on post-marketing adverse reactions.c Infusion-related reactions includes terms determined by investigators as related to infusion/injection ofdaratumumab.d Injection site reactions includes terms determined by investigators as related to injection of daratumumab.e Frequency based on daratumumab subcutaneous studies only (N=1380).f Frequency based on daratumumab intravenous studies only (N=2324).g Incidence is based on a subset of patients who received at least one dose of study treatment on or after 01 February2020 (the start of the COVID-19 pandemic) from studies MMY3003, MMY3006, MMY3008 and MMY3013, andall daratumumab treated patients from studies MMY3014 and MMY3019 (N=984).

Note: Based on 3704 multiple myeloma and AL amyloidosis patients treated with daratumumab intravenous ordaratumumab subcutaneous.

In clinical studies (monotherapy and combination treatments; N=1380) with DARZALEXsubcutaneous formulation, the incidence of any grade IRRs was 6.4% with the first injection of

DARZALEX (1800 mg, week 1), 0.3% with the week 2 injection, and 1.2% with subsequentinjections. Grades 3 and 4 IRRs were seen in 0.7% and 0.1% of patients, respectively.

Signs and symptoms of IRR 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. Severe reactions have occurred, including bronchospasm,hypoxia, dyspnoea, hypertension, tachycardia and ocular adverse reactions (including choroidaleffusion, acute myopia and acute angle closure glaucoma) (see section 4.4).

Injection site reactions (ISRs)

In clinical studies (N=1380) with DARZALEX subcutaneous formulation, the incidence of any gradeinjection site reaction was 7.8%. There were no grade 3 or 4 ISRs. The most common (> 1%) ISR atthe site of injection was erythema and rash.

In patients with multiple myeloma receiving daratumumab as monotherapy, the overall incidence ofinfections was similar between DARZALEX subcutaneous formulation (52.9%) versus intravenousdaratumumab groups (50.0%). Grade 3 or 4 infections also occurred at similar frequencies between

DARZALEX subcutaneous formulation (11.7%) and intravenous daratumumab (14.3%). Mostinfections were manageable and rarely led to treatment discontinuation. Pneumonia was the mostcommonly reported grade 3 or 4 infection across studies. In active-controlled studies, discontinuationsfrom treatment due to infections occurred in 1-4% of patients. Fatal infections were primarily due topneumonia and sepsis.

In patients with multiple myeloma receiving intravenous daratumumab combination therapy, thefollowing were reported:

Grade 3 or 4 infections:

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

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

VTd: 20%.

Grade 5 (fatal) infections:

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

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

In patients with multiple myeloma receiving DARZALEX subcutaneous formulation combinationtherapy, the following were reported:

Grade 3 or 4 infections: DPd: 28%, Pd: 23%; D-VRd (transplant eligible): 35%, VRd (transplanteligible): 27%; D-VRd (transplant ineligible):40%, VRd (transplant ineligible): 32%

Grade 5 (fatal) infections: DPd: 5%, Pd: 3%; D-VRd (transplant eligible): 2%, VRd (transplanteligible): 3%; D-VRd (transplant ineligible):8%, VRd (transplant ineligible): 6%

Key: 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 AL amyloidosis receiving DARZALEX subcutaneous formulation combinationtherapy, the following were reported:

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

Grade 5 infections: D-VCd: 1%, VCd: 1%

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

Haemolysis

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

Cardiac disorders and AL amyloidosis-related cardiomyopathy

The majority of patients in AMY3001 had AL amyloidosis-related cardiomyopathy at baseline(D-VCd 72% vs. VCd 71%). Grade 3 or 4 cardiac disorders occurred in 11% of D-VCd patientscompared to 10% of VCd patients, while serious cardiac disorders occurred in 16% vs. 13% of D-VCdand VCd patients, respectively. Serious cardiac disorders occurring in ≥ 2% of patients includedcardiac failure (D-VCd 6.2% vs. VCd 4.3%), cardiac arrest (D-VCd 3.6% vs. VCd 1.6%) and atrialfibrillation (D-VCd 2.1% vs. VCd 1.1%). All D-VCd patients who experienced serious or fatal cardiacdisorders had AL amyloidosis-related cardiomyopathy at baseline. The longer median duration oftreatment in the D-VCd arm compared to the VCd arm (9.6 months vs. 5.3 months, respectively)should be taken into consideration when comparing the frequency of cardiac disorders between thetwo treatment groups. Exposure-adjusted incidence rates (number of patients with the event per100 patient-months at risk) of overall grade 3 or 4 cardiac disorders (1.2 vs. 2.3), cardiac failure (0.5vs. 0.6), cardiac arrest (0.1 vs. 0.0) and atrial fibrillation (0.2 vs. 0.1) were comparable in the D-VCdarm vs. the VCd arm, respectively.

With a median follow-up of 11.4 months, overall deaths (D-VCd 14% vs. VCd 15%) in study

AMY3001 were primarily due to AL amyloidosis-related cardiomyopathy in both treatment arms.

In the phase III study MMY3007, which compared treatment with D-VMP to treatment with VMP inpatients with newly diagnosed multiple myeloma who are ineligible for autologous stem celltransplant, safety analysis of the subgroup of patients with an ECOG performance score of 2(D-VMP: n=89, VMP: n=84), was consistent with the overall population (see section 5.1).

Of the 4238 patients who received daratumumab (n=1422 subcutaneous; n=2816 intravenous) at therecommended dose, 38% were 65 to less than 75 years of age, and 15% were 75 years of age or older.

No overall differences in effectiveness were observed based on age. The incidence of serious adversereactions was higher in older than in younger patients. Among patients with relapsed and refractorymultiple myeloma (n=1976), the most common serious adverse reactions that occurred morefrequently in elderly (≥ 65 years of age) were pneumonia and sepsis. Among patients with newlydiagnosed multiple myeloma who were ineligible for autologous stem cell transplant (n=777), themost common serious adverse reaction that occurred more frequently in elderly (≥ 75 years of age)was pneumonia. Among patients with newly diagnosed multiple myeloma who were eligible forautologous stem cell transplant (n=351), the most common serious adverse reaction that occurred morefrequently in elderly (≥ 65 years of age) was pneumonia. Among patients with newly diagnosedmultiple myeloma for whom transplant was not planned as initial therapy or who were ineligible forautologous stem cell transplant (n=197), the most common serious adverse reaction that occurred morefrequently in elderly (≥ 65 years of age) was pneumonia. Among patients with newly diagnosed ALamyloidosis (n=193), the most common serious adverse reaction that occurred more frequently inelderly (≥ 65 years of age) was pneumonia.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms and signs

There has been no experience of overdose in clinical studies.

There is no known specific antidote for daratumumab overdose. In the event of an overdose, thepatient should be monitored for any signs or symptoms of adverse reactions and appropriatesymptomatic treatment should be instituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, CD38 (Clusters of Differentiation 38) inhibitors, ATC code: L01FC01.

DARZALEX solution for subcutaneous injection contains recombinant human hyaluronidase(rHuPH20). rHuPH20 works locally and transiently to degrade hyaluronan ((HA), a naturallyoccurring glycoaminoglycan found throughout the body) in the extracellular matrix of thesubcutaneous space by cleaving the linkage between the two sugars (N-acetylglucosamine andglucuronic acid) which comprise HA. rHuPH20 has a half-life in skin of less than 30 minutes.

Hyaluronan levels in subcutaneous tissue return to normal within 24 to 48 hours because of the rapidbiosynthesis of hyaluronan.

Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to the CD38 proteinexpressed on the surface of cells in a variety of haematological malignancies, including clonal plasmacells in multiple myeloma and AL amyloidosis, as well as other cell types and tissues. CD38 proteinhas multiple functions such as receptor mediated adhesion, signalling and enzymatic activity.

Daratumumab has been shown to potently inhibit the in vivo growth of CD38-expressing tumour cells.

Based on in vitro studies, daratumumab may utilise multiple effector functions, resulting in immunemediated tumour cell death. These studies suggest that daratumumab can induce tumour cell lysisthrough complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, andantibody-dependent cellular phagocytosis in malignancies expressing CD38. A subset of myeloidderived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs)are decreased by daratumumab mediated cell lysis. T cells (CD3+, CD4+, and CD8+) are also knownto express CD38 depending on the stage of development and the level of activation. Significantincreases in CD4+ and CD8+ T cell absolute counts, and percentages of lymphocytes, were observedwith daratumumab treatment in peripheral whole blood and bone marrow. In addition, T-cell receptor

DNA sequencing verified that T-cell clonality was increased with daratumumab treatment, indicatingimmune modulatory effects that may contribute to clinical response.

Daratumumab induced apoptosis in vitro after Fc mediated cross-linking. In addition, daratumumabmodulated CD38 enzymatic activity, inhibiting the cyclase enzyme activity and stimulating thehydrolase activity. The significance of these in vitro effects in a clinical setting, and the implicationson tumour growth, are not well-understood.

Natural killer (NK) cell and T-cell count

NK cells are known to express high levels of CD38 and are susceptible to daratumumab mediated celllysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated(CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed withdaratumumab treatment. However, baseline levels of NK cells did not show an association withclinical response.

In multiple myeloma and AL amyloidosis patients treated with subcutaneous daratumumab inmonotherapy and combination clinical studies, less than 1% of patients developed treatment-emergentanti-daratumumab antibodies and 7 patients tested positive for neutralising antibodies.

In multiple myeloma and AL amyloidosis patients, the incidence of treatment-emergentnon-neutralising anti-rHuPH20 antibodies was 8.9% (115/1298) in patients who received eithermonotherapy DARZALEX subcutaneous formulation or combination DARZALEX subcutaneousformulation and 1 patient tested positive for neutralising antibodies. The anti-rHuPH20 antibodies didnot appear to impact daratumumab exposures. The clinical relevance of the development ofanti-daratumumab or anti-rHuPH20 antibodies after treatment with DARZALEX subcutaneousformulation is not known.

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

Monotherapy - relapsed/refractory multiple myeloma

MMY3012, an open-label, randomised, phase III non-inferiority study, compared efficacy and safetyof treatment with DARZALEX solution for subcutaneous injection (1800 mg) vs. intravenous(16 mg/kg) daratumumab in patients with relapsed or refractory multiple myeloma who had receivedat 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 unacceptabletoxicity or disease progression.

A total of 522 patients were randomised: 263 to the DARZALEX subcutaneous formulation arm and259 to the intravenous daratumumab arm. The baseline demographic and disease characteristics weresimilar between the two treatment groups. The median patient age was 67 years (range: 33-92 years),55% were male and 78% were Caucasian. The median patient weight was 73 kg (range: 29 - 138 kg)

Patients had received a median of 4 prior lines of therapy. A total of 51% of patients had priorautologous stem cell transplant (ASCT), 100% of patients were previously treated with both PI(s) and

IMiD(s) and most patients were refractory to a prior systemic therapy, including both PI and IMiD(49%).

The study met its co-primary endpoints of overall response rate (ORR) by the IMWG response criteria(table 9) and maximum Ctrough at pre-dose cycle 3 day 1, (see section 5.2).

Table 9: Key results from study MMY3012

Subcutaneous Intravenousdaratumumab daratumumab(N=263) (N=259)

Primary endpoint

Overall response (sCR+CR+VGPR+PR), n (%)a 108 (41.1%) 96 (37.1%)95% CI (%) (35.1%, 47.3%) (31.2%, 43.3%)

Ratio of response rates (95% CI)b 1.11 (0.89, 1.37)

CR or better, n (%) 5 (1.9%) 7 (2.7%)

Very good partial response (VGPR) 45 (17.1%) 37 (14.3%)

Partial response (PR) 58 (22.1%) 52 (20.1%)

Secondary endpoint

Rate of infusion-related reaction, n (%)c 33 (12.7%) 89 (34.5%)

Progression-free survival, months

Median (95% CI) 5.59 (4.67, 7.56) 6.08 (4.67, 8.31)

Hazard ratio (95% CI) 0.99 (0.78, 1.26)a Based on intent-to-treat population.b p-value < 0.0001 from Farrington-Manning test for non-inferiority hypothesis.c Based on safety population. P-value< 0.0001 from Cochran-Mantel-Haenszel Chi-Squared test.

After a median follow-up of 29.3 months, the median OS was 28.2 months (95% CI: 22.8, NE) in the

DARZALEX subcutaneous formulation arm and was 25.6 months (95% CI: 22.1, NE) in theintravenous daratumumab arm.

Safety and tolerability results, including in lower weight patients, were consistent with the knownsafety profile for DARZALEX subcutaneous formulation and intravenous daratumumab.

Results from the modified-CTSQ, a patient reported outcome questionnaire that assesses patientsatisfaction with their therapy, demonstrated that patients receiving DARZALEX subcutaneousformulation had greater satisfaction with their therapy compared with patients receiving intravenousdaratumumab. However, open-label studies are subject to bias.

Combination therapies in multiple myeloma

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

Study MMY3014 was an open-label, randomised, active-controlled phase III study that comparedinduction and consolidation treatment with DARZALEX subcutaneous formulation (1800 mg) incombination with bortezomib, lenalidomide and dexamethasone (D-VRd), followed by maintenancewith DARZALEX in combination with lenalidomide, to treatment with bortezomib, lenalidomide anddexamethasone (VRd), followed by maintenance with lenalidomide, in patients 70 years of age andyounger with newly diagnosed multiple myeloma eligible for ASCT until documented diseaseprogression or unacceptable toxicity. An emergency short course of corticosteroid (equivalent ofdexamethasone 40 mg/day for a maximum 4 days) was permitted before treatment. Patients received

DARZALEX subcutaneous formulation (1800 mg) administered subcutaneously 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. Formaintenance (cycles 7+), patients received DARZALEX subcutaneous formulation (1800 mg) onceevery four weeks. Patients who achieved MRD negativity that was sustained for 12 months and hadbeen treated on maintenance for at least 24 months discontinued treatment with DARZALEXsubcutaneous formulation (1800 mg). Bortezomib was administered by subcutaneous (SC) injection ata dose of 1.3 mg/m2 body surface area twice weekly for two weeks (days 1, 4, 8, and 11) of repeated28-day (4-week) cycles 1-6. Lenalidomide was administered orally at 25 mg daily on days 1 to 21during cycles 1-6. For maintenance (cycles 7+), patients received 10 mg lenalidomide daily ondays 1-28 (continuously) of each cycle until documented disease progression or unacceptable toxicity.

Dexamethasone (oral or intravenous) was administered at 40 mg on days 1-4 and days 9-12 ofcycles 1-6. On the days of DARZALEX subcutaneous formulation (1800 mg) injection, thedexamethasone dose was administered orally or intravenously as a pre-injection medicinal product.

Dose adjustments for bortezomib, lenalidomide and dexamethasone were applied according tomanufacturer’s prescribing information.

A total of 709 patients were randomised: 355 to the D-VRd arm and 354 to the VRd arm. The baselinedemographic and disease characteristics were similar between the two treatment groups. The medianage was 60 (range: 31 to 70 years). The majority were male (59%), 64% had an ECOG performancescore of 0, 31% had an ECOG performance score of 1 and 5% had an ECOG performance score of 2.

Additionally, 51% had ISS stage I, 34% had ISS stage II, 15% had ISS stage III disease, 75% had astandard cytogenetic risk, 22% had a high cytogenetic risk (del17p, t[4;14], t[14;16]), and 3% had anindeterminate cytogenetic risk.

With a median follow-up of 47.5 months, the primary analysis of PFS in study MMY3014demonstrated an improvement in PFS in the D-VRd arm as compared to the VRd arm (HR=0.42; 95%

CI: 0.30, 0.59; p<0.0001). The median PFS was not reached in either arm.

Figure 1: Kaplan-Meier curve of PFS in study MMY3014

Additional efficacy results from study MMY3014 are presented in table 10 below.

Table 10: Efficacy results from study MMY3014a

D-VRd (n=355) VRd (n=354) Odds ratio(95% CI)d

Overall response (sCR+CR+VGPR+PR)n(%)a 343 (96.6%) 332 (93.8%)

Stringent complete response (sCR) 246 (69.3%) 158 (44.6%)

Complete response (CR) 66 (18.6%) 90 (25.4%)

Very good partial response (VGPR) 26 (7.3%) 68 (19.2%)

Partial response (PR) 5 (1.4%) 16 (4.5%)

CR or better (sCR+CR) 312 (87.9%) 248 (70.1%) 3.13 (2.11, pct. 4.65)95% CI (%) (84.0%, 91.1%) (65.0%, 74.8%)

P-valueb < 0.0001

Overall MRD negativity ratea,c 267 (75.2%) 168 (47.5%) 3.40 (2.47, pct. 4.69)95% CI (%) (70.4%, 79.6%) (42.2%, 52.8%)

P-valueb < 0.0001

D-VRd=daratumumab-bortezomib-lenalidomide-dexamethasone; VRd=bortezomib-lenalidomide-dexamethasone;

MRD=minimal residual disease; CI=confidence intervala Based on intent-to-treat populationb p-value from Cochran Mantel-Haenszel Chi-Squared testc Patients achieved both MRD negativity (threshold of 10-5) and CR or betterd Mantel-Haenszel estimate of the common odds ratio for stratified tables is used

Combination treatment with bortezomib, lenalidomide and dexamethasone (VRd) in patients withnewly diagnosed multiple myeloma for whom ASCT is not planned as initial therapy or who areineligible for ASCT

Study MMY3019 was an open-label, randomised, active-controlled phase III study that comparedtreatment with DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib,lenalidomide and dexamethasone (D-VRd) to treatment with bortezomib, lenalidomide anddexamethasone (VRd) in patients with newly diagnosed multiple myeloma for whom ASCT was notplanned as initial therapy or who were not eligible for ASCT. An emergency short course ofcorticosteroid (equivalent of dexamethasone 40 mg/day for a maximum 4 days) was permitted beforetreatment. Patients received DARZALEX subcutaneous formulation (1800 mg) administeredsubcutaneously once weekly (days 1, 8, and 15) for cycles 1 to 2 followed by once every three weeksfor cycles 3 to 8, and once every four weeks in cycle 9 and beyond until documented diseaseprogression or unacceptable toxicity. Bortezomib was administered by subcutaneous injection at adose of 1.3 mg/m2 body surface area twice weekly (days 1, 4, 8, and 11) of repeated 21-day (3-week)cycles 1-8. Lenalidomide was administered orally at 25 mg daily on days 1 to 14 during cycles 1-8 andon days 1-21 during cycle 9 and beyond. Dexamethasone was administered orally at 20 mg on days 1,2, 4, 5, 8, 9, 11, and 12 of each 21-day (3-week ) cycles 1-8 and days 1, 8, 15, and 22 of each 28-day(4-week) during cycle 9 and beyond. On the days of DARZALEX subcutaneous formulation(1800 mg) injection, the dexamethasone dose was administered orally or intravenously as apre-injection medication. Dose adjustments for bortezomib, lenalidomide and dexamethasone wereapplied according to manufacturer’s prescribing information.

A total of 395 patients were randomised: 197 to the D-VRd arm and 198 to the VRd arm. The baselinedemographic and disease characteristics were similar between the two treatment groups. The medianage was 70 (range: 31 to 80 years). Fifty percent were male, 39% had an ECOG performance score of0, 51% had an ECOG performance score of 1 and 9% had an ECOG performance score of 2. Eighteenpercent were less than 70 years of age and transplant ineligible and 27% were less than 70 years of ageand were transplant deferred. Additionally, 34% had ISS stage I, 38% had ISS stage II, 28% had ISSstage III disease, 75% had a standard cytogenetic risk, 13% had a high cytogenetic risk (del17p,t[4;14], t[14;16]), and 11% had an indeterminate cytogenetic risk.

With a median follow-up of 22.3 months, the primary analysis of MRD in study MMY3019demonstrated an improvement in overall MRD negativity rate (by NGS at or below 10-5) for patientsreaching CR or better in the D-VRd arm as compared to the VRd arm. Overall MRD negativity rateswere 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 primary MRD analysis, an improvement in overall CR or better rate was observed in the

D-VRd arm as compared to the VRd arm. Overall CR or better rates 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; 95% CI: 1.48, 3.60; p=0.0002).

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

Figure 2: Kaplan-Meier curve of PFS at final analysis in study MMY3019

At the time of interim PFS analysis, an improvement in 1-year sustained MRD negativity rate (by

NGS at or below 10-5) for patients reaching CR or better was observed in the D-VRd arm as comparedto the VRd arm. Sustained MRD negativity rates were 42.6% (95% CI: 35.6, 49.9) in the D-VRd armand 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).

Additional efficacy results from Study MMY3019 are presented in table 11 below.

Table 11: Efficacy results from the final PFS analysis of study MMY3019a

D-VRd (n=197) VRd (n=198)

Overall MRD negativity rateb 120 (60.9%) 78 (39.4%)

Odds ratio (95% CI)c 2.37 (1.58, 3.55)

Sustained MRD negativity rated 96 (48.7%) 52 (26.3%)

Odds ratio (95% CI)c 2.63 (1.73, 4.00)

Overall CR or better (sCR+CR) 160 (81.2%) 122 (61.6%)

Odds ratio (95% CI)c 2.73 (1.71, pct. 4.34)

Overall response (sCR+CR+VGPR+PR) n (%)a 191 (97.0%) 184 (92.9%)

Stringent complete response (sCR) 128 (65.0%) 88 (44.4%)

Complete response (CR) 32 (16.2%) 34 (17.2%)

Very good partial response (VGPR) 23 (11.7%) 50 (25.3%)

Partial response (PR) 8 (4.1%) 12 (6.1%)

D-VRd=daratumumab-bortezomib-lenalidomide-dexamethasone; VRd=bortezomib-lenalidomide-dexamethasone;

MRD=minimal residual disease; CI=confidence intervala Based on intent-to-treat population, median follow-up of 59 monthsb Patients achieved both MRD negativity (threshold of at or below 10-5) and CR or betterc Mantel-Haenszel estimate of the common ratio for stratified tables is used. The stratification factors are: ISS staging (I,

II, III), age/transplant eligibility (< 70 years ineligible, or age< 70 years and refusal to transplant, or age ≥ 70 years) asrandomised. An odds ratio > 1 indicates an advantage for D-VRd.

d Sustained MRD negativity is defined as MRD negative and confirmed by at least 1 year apart without MRD positive inbetween.

Combination therapies in multiple myeloma

MMY2040 was an open-label study evaluating the efficacy and safety of DARZALEX subcutaneousformulation 1800 mg:

- in combination with bortezomib, melphalan, and prednisone (D-VMP) in patients with newlydiagnosed multiple myeloma (MM) who are ineligible for transplant. Bortezomib wasadministered by subcutaneous injection at a dose of 1.3 mg/m2 body surface area twice weeklyat weeks 1, 2, 4 and 5 for the first 6-week cycle (cycle 1; 8 doses), followed by once weeklyadministrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles (cycles 2-9; 4 doses percycle). Melphalan at 9 mg/m2, and prednisone at 60 mg/m2 were orally administered on days 1to 4 of the nine 6-week cycles (cycles 1-9). DARZALEX subcutaneous formulation wascontinued until disease progression or unacceptable toxicity.

- in combination with lenalidomide and dexamethasone (D-Rd) in patients with relapsed orrefractory MM. Lenalidomide (25 mg once daily orally on days 1-21 of repeated 28-day[4-week] cycles) was given with low dose dexamethasone 40 mg/week (or a reduced dose of20 mg/week for patients > 75 years or BMI < 18.5). DARZALEX subcutaneous formulationwas continued until disease progression or unacceptable toxicity.

- in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients withnewly diagnosed MM who are transplant eligible. Bortezomib was administered bysubcutaneous injection at a dose of 1.3 mg/m2 body surface area twice weekly at weeks 1 and 2.

Lenalidomide was administered orally at 25 mg once daily on days 1-14; low dosedexamethasone was administered 40 mg/week in 3-week cycles. Total treatment duration was4 cycles.

A total of 199 patients (D-VMP: 67; D-Rd: 65; D-VRd: 67) were enrolled. Efficacy results weredetermined by computer algorithm using IMWG criteria. The study met its primary endpoint ORR for

D-VMP and D-Rd and the primary endpoint VGPR or better for D-VRd (see table 12).

Table 12: Efficacy results from study MMY2040

D-VMP (n=67) D-Rd (n=65) D-VRd (n=67)

Overall response 60 (89.6%) 61 (93.8%) 65 (97.0%)(sCR+CR+VGPR+PR), n (%)a90% CI(%) (81.3%, 95.0%) (86.5%, 97.9%) (90.9%, 99.5%)

Stringent complete response (sCR) 13 (19.4%) 12 (18.5%) 6 (9.0%)

Complete response (CR) 19 (28.4%) 13 (20.0%) 5 (7.5%)

Very good partial response (VGPR) 20 (29.9%) 26 (40.0%) 37 (55.2%)

Partial response (PR) 8 (11.9%) 10 (15.4%) 17 (25.4%)

VGPR or better (sCR + CR + VGPR) 52 (77.6%) 51 (78.5%) 48 (71.6%)90% CI(%) (67.6%, 85.7%) (68.4%, 86.5%) (61.2%, 80.6%)

D-VMP=Daratumumab-bortezomib-melphalan-prednisone; D-Rd=Daratumumab-lenalidomide-dexamethasone; D-

VRd=Daratumumab-bortezomib-lenalidomide-dexamethasone; Daratumumab=DARAZALEX subcutaneous formulation;

CI=confidence interval.a Based on treated subjects.

Combination treatment with pomalidomide and dexamethasone (Pd)

Study MMY3013 was an open-label, randomised, active-controlled phase III study that comparedtreatment with DARZALEX subcutaneous formulation (1800 mg) in combination with pomalidomideand low-dose dexamethasone (D-Pd) to treatment with pomalidomide and low-dose dexamethasone(Pd) in patients with multiple myeloma who had received at least one prior line of therapy withlenalidomide and a proteasome inhibitor (PI). Pomalidomide (4 mg once daily orally on days 1-21 ofrepeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone40 mg/week (or a reduced dose of 20 mg/week for patients > 75 years). On DARZALEXsubcutaneous formulation administration days, 20 mg of the dexamethasone dose was given as a pre-administration medicinal product and the remainder given the day after the administration. For patientson a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX subcutaneousformulation pre-administration medicinal product. Dose adjustments for pomalidomide anddexamethasone were applied according to manufacturer’s prescribing information. Treatment wascontinued in both arms until disease progression or unacceptable toxicity.

A total of 304 patients were randomised: 151 to the D-Pd arm and 153 to the Pd arm. Patients withdocumented evidence of disease progression on or after the last regimen were included in the study.

Patients who had ≥ grade 3 rash during prior therapy were excluded as per the pomalidomide

Summary of Product Characteristics. The baseline demographic and disease characteristics weresimilar between the two treatment groups. The median patient age was 67 years (range 35 to 90 years),18% were ≥ 75 years, 53% were male, and 89% Caucasian. Patients had received a median of 2 priorlines of therapy. All patients received a prior treatment with a proteasome inhibitor (PI) andlenalidomide, and 56% of patients received prior stem cell transplantation (ASCT). Ninety-six percent(96%) of patients received prior treatment with bortezomib. The majority of patients were refractory tolenalidomide (80%), a PI (48%), or both an immunomodulator and a PI (42%). Eleven percent ofpatients received 1 prior line of therapy; all were refractory to lenalidomide and 32.4% were refractoryto both lenalidomide and a PI. Efficacy was evaluated by progression free survival (PFS) based on

International Myeloma Working Group (IMWG) criteria.

With a median follow-up of 16.9 months, the primary analysis of PFS in study MMY3013 showed astatistically significant improvement in the D-Pd arm as compared to the Pd arm; the median PFS was12.4 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 patientstreated with D-Pd versus Pd.

Figure 3: Kaplan-Meier curve of PFS in study MMY3013

An additional planned follow-up analysis of OS after a median follow-up of 39.6 months wasperformed. At OS maturity of 57%, the median OS was 34.4 months in the D-Pd arm and 23.7 monthsin the Pd arm (HR [95% CI]: 0.82 [0.61, 1.11]).

Additional efficacy results from study MMY3013 are presented in table 13 below.

Table 13: Efficacy results from study MMY3013a

D-Pd (n=151) Pd (n=153)

Overall response (sCR+CR+VGPR+PR) n(%)a 104 (68.9%) 71 (46.4%)

P-valueb < 0.0001

Stringent complete response (sCR) 14 (9.3%) 2 (1.3%)

Complete response (CR) 23 (15.2%) 4 (2.6%)

Very good partial response (VGPR) 40 (26.5%) 24 (15.7%)

Partial response (PR) 27 (17.9%) 41 (26.8%)

MRD negativity ratec n(%) 13 (8.7%) 3 (2.0%)95% CI (%) (4.7%, 14.3%) (0.4%, 5.6%)

P-valued 0.0102

D-Pd=daratumumab-pomalidomide-dexamethasone; Pd=pomalidomide-dexamethasone; MRD=minimal residual disease;

CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors.c MRD Negative rate is based on the intent-to-treat population and a threshold of 10-5.d p-value from Fisher’s exact test.

In responders, the median time to response was 1 month (range: 0.9 to 9.1 months) in the D-Pd groupand 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had notbeen reached in the D-Pd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to24.8 months) in the Pd group.

Combination treatment with bortezomib, cyclophosphamide and dexamethasone in patients with ALamyloidosis

Study AMY3001, an open-label, randomised, active-controlled phase III study, compared treatmentwith DARZALEX subcutaneous formulation (1800 mg) in combination with bortezomib,cyclophosphamide and dexamethasone (D-VCd) to treatment with bortezomib, cyclophosphamide anddexamethasone (VCd) alone in patients with newly diagnosed systemic AL amyloidosis.

Randomisation was stratified by AL amyloidosis Cardiac Staging System, countries that typicallyoffer autologous stem cell transplant (ASCT) for patients with AL amyloidosis, and renal function.

All patients enrolled in study AMY3001 had newly diagnosed AL amyloidosis with at least oneaffected organ, measurable hematologic disease, cardiac stage I-IIIA (based on European Modificationof Mayo 2004 cardiac stage), and NYHA class I-IIIA. Patients with NYHA class IIIB and IV wereexcluded.

Bortezomib (SC; 1.3 mg/m2 body surface area), cyclophosphamide (oral or IV; 300 mg/m2 bodysurface area; max dose 500 mg), and dexamethasone (oral or IV; 40 mg or a reduced dose of 20 mgfor patients > 70 years or body mass index [BMI] < 18.5 or those who have hypervolemia, poorlycontrolled diabetes mellitus or prior intolerance to steroid therapy) were administered weekly ondays 1, 8, 15, and 22 of repeated 28-day [4-week] cycles. On the days of DARZALEX dosing, 20 mgof the dexamethasone dose was given as a pre-injection medicinal product and the remainder given theday after DARZALEX administration. Bortezomib, cyclophosphamide and dexamethasone were givenfor six 28-day [4-week] cycles in both treatment arms, while DARZALEX treatment was continueduntil disease progression, start of subsequent therapy, or a maximum of 24 cycles (~2 years) from thefirst dose of study treatment. Dose adjustments for bortezomib, cyclophosphamide and dexamethasonewere applied according to manufacturer’s prescribing information.

A total of 388 patients were randomised: 195 to the D-VCd arm and 193 to the VCd arm. The baselinedemographic and disease characteristics were similar between the two treatment groups. The majority(79%) of patients had lambda free light chain disease. The median patient age was 64 years (range: 34to 87); 47% were ≥ 65 years; 58% were male; 76% Caucasian, 17% Asian, and 3% African American;23% had AL amyloidosis Clinical Cardiac stage I, 40% had stage II, 35% had stage IIIA, and 2% hadstage IIIB. All patients had one or more affected organs and the median number of organs involvedwas 2 (range: 1-6) and 66% of patients had 2 or more organs involved. Vital organ involvement was:71% cardiac, 59% renal and 8% hepatic. Patients with grade 2 sensory or grade 1 painful peripheralneuropathy were excluded. The primary efficacy endpoint was hematologic complete response(HemCR) rate as determined by the Independent Review Committee assessment based on

International Concensus Criteria. Study AMY3001 demonstrated an improvement in HemCR in the

D-VCd arm as compared to the VCd arm. Efficacy results are summarised in table 14.

Table 14: Efficacy results from study AMY3001a

D-VCd VCd P value(n=195) (n=193)

Hematologic complete response (HemCR), n (%) 104 (53.3%) 35 (18.1%) < 0.0001b

Very good partial response (VGPR), n (%) 49 (25.1%) 60 (31.1%)

Partial response (PR), n (%) 26 (13.3%) 53 (27.5%)

Hematologic VGPR or better (HemCR + VGPR), n (%) 153 (78.5%) 95 (49.2%) < 0.0001b

Major organ deterioration progression-free survival 0.58 (0.36, 0.93) 0.0211d(MOD-PFS), Hazard ratio with 95% CIc

D-VCd=daratumumab-bortezomib-cyclophosphamide-dexamethasone; VCd=bortezomib-cyclophosphamide-dexamethasone.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c MOD-PFS defined as hematologic progression, major organ (cardiac or renal) deterioration or death.d Nominal p-value from inverse probability censoring weighted log-rank test.

In responders, the median time to HemCR was 60 days (range: 8 to 299 days) in the D-VCd group and85 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. Themedian duration of HemCR had not been reached in either arm.

The median follow-up for the study is 11.4 months. The median major organ deteriorationprogression-free survival (MOD-PFS) was not reached for patients in either arm.

Overall survival (OS) data were not mature. A total of 56 deaths were observed [n=27 (13.8%) D-VCdvs. n=29 (15%) VCd group].

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

Newly diagnosed multiple myeloma

Combination treatment with lenalidomide and dexamethasone in patients ineligible for autologousstem cell transplant

Study MMY3008, an open-label, randomised, active-controlled phase III study, compared treatmentwith intravenous daratumumab 16 mg/kg in combination with lenalidomide and low-dosedexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patientswith newly diagnosed multiple myeloma. Lenalidomide (25 mg once daily orally on days 1-21 ofrepeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index[BMI] < 18.5). On intravenous daratumumab infusion days, the dexamethasone dose was given as apre-infusion medicinal product. Dose adjustments for lenalidomide and dexamethasone were appliedaccording to manufacturer’s prescribing information. Treatment was continued in both arms untildisease progression or unacceptable toxicity.

A total of 737 patients were randomised: 368 to the DRd arm and 369 to the Rd arm. The baselinedemographic and disease characteristics were similar between the two treatment groups. The medianage was 73 (range: 45-90) years, with 44% of the patients ≥ 75 years of age. The majority were white(92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of0, 49.5% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥ 2.

Twenty-seven percent had International Staging System (ISS) stage I, 43% had ISS stage II and 29%had ISS stage III disease. Efficacy was evaluated by progression free survival (PFS) based on

International Myeloma Working Group (IMWG) criteria and overall survival (OS).

With a median follow-up of 28 months, the primary analysis of PFS in study MMY3008 showed animprovement in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the

DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73;p < 0.0001), representing 44% reduction in the risk of disease progression or death in patients treatedwith DRd. Results of an updated PFS analysis after a median follow-up of 64 months continued toshow an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFSwas 61.9 months in the DRd arm and 34.4 months in the Rd arm (HR=0.55; 95% CI: 0.45, 0.67).

Figure 4: Kaplan-Meier curve of PFS in study MMY3008

With a median follow-up of 56 months, DRd has shown an OS advantage over the Rd arm (HR=0.68;95% CI: 0.53, 0.86; p=0.0013). Results of an updated OS analysis after a median of 89 monthscontinued to show an improvement in OS for patients in the DRd arm compared to the Rd arm.

Median OS was 90.3 months in the DRd arm and was 64.1 months in the Rd arm (HR= 0.67;95% CI: 0.55, 0.82).

Figure 5: Kaplan-Meier curve of OS in study MMY3008

Additional efficacy results from study MMY3008 are presented in table 15 below.

Table 15: Additional efficacy results from study MMY3008a

DRd (n=368) Rd (n=369)

Overall response (sCR+CR+VGPR+PR) n(%)a 342 (92.9%) 300 (81.3%)p-valueb < 0.0001

Stringent complete response (sCR) 112 (30.4%) 46 (12.5%)

Complete response (CR) 63 (17.1%) 46 (12.5%)

Very good partial response (VGPR) 117 (31.8%) 104 (28.2%)

Partial response (PR) 50 (13.6%) 104 (28.2%)

CR or better (sCR + CR) 175 (47.6%) 92 (24.9%)p-valueb < 0.0001

VGPR or better (sCR + CR + VGPR) 292 (79.3%) 196 (53.1%)p-valueb < 0.0001

MRD negativity ratea,c n(%) 89 (24.2%) 27 (7.3%)95% CI (%) (19.9%, 28.9%) (4.9%, 10.5%)

Odds ratio with 95% CId 4.04 (2.55, 6.39)p-valuee < 0.0001

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease;

CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c Based on threshold of 10-5.d Mantel-Haenszel estimate of the odds ratio for un-stratified tables is used. An odds ratio > 1 indicates an advantage for

DRd.e p-value from Fisherʼs exact test.

In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRdgroup and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of responsehad not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rdgroup.

Combination treatment with bortezomib, melphalan and prednisone (VMP) in patients ineligible forautologous stem cell transplant

Study MMY3007, an open-label, randomised, active-controlled phase III study, compared treatmentwith intravenous daratumumab 16 mg/kg in combination with bortezomib, melphalan and prednisone(D-VMP), to treatment with VMP in patients with newly diagnosed multiple myeloma. Bortezomibwas administered by subcutaneous injection at a dose of 1.3 mg/m2 body surface area twice weekly atweeks 1, 2, 4 and 5 for the first 6-week cycle (cycle 1; 8 doses), followed by once weeklyadministrations at weeks 1, 2, 4 and 5 for eight more 6-week cycles (cycles 2-9; 4 doses per cycle).

Melphalan at 9 mg/m2, and prednisone at 60 mg/m2 were orally administered on days 1 to 4 of the nine6-week cycles (cycles 1-9). Intravenous daratumumab treatment was continued until diseaseprogression or unacceptable toxicity.

A total of 706 patients were randomised: 350 to the D-VMP arm and 356 to the VMP arm. Thebaseline demographic and disease characteristics were similar between the two treatment groups. Themedian age was 71 (range: 40-93) years, with 30% of the patients ≥ 75 years of age. The majoritywere white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOGperformance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Lightchain myeloma in 64%/22%/10% of instances, 19% had ISS stage I, 42% had ISS stage II, 38% had

ISS stage III disease and 84% had standard risk cytogenetics. Efficacy was evaluated by PFS based on

IMWG criteria and overall survival (OS).

With a median follow-up of 16.5 months, the primary analysis of PFS in study MMY3007 showed animprovement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reachedin 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).

Results of an updated PFS analysis after a median follow-up of 40 months continued to show animprovement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was36.4 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), representing a 58% reduction in the risk of disease progression or death in patients treatedwith D-VMP.

Figure 6: Kaplan-Meier curve of PFS in study MMY3007

After a median follow-up of 40 months, D-VMP has shown an OS advantage over the VMP arm(HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patientstreated in the D-VMP arm. After a median follow-up of 87 months, the 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.

Figure 7: Kaplan-Meier curve of OS in study MMY3007

Additional efficacy results from study MMY3007 are presented in table 16 below.

Table 16: Additional efficacy results from study MMY3007a

D-VMP (n=350) VMP (n=356)

Overall response (sCR+CR+VGPR+PR) [n(%)] 318 (90.9) 263 (73.9)p-valueb < 0.0001

Stringent complete response (sCR) [n(%)] 63 (18.0) 25 (7.0)

Complete response (CR) [n(%)] 86 (24.6) 62 (17.4)

Very good partial response (VGPR) [n(%)] 100 (28.6) 90 (25.3)

Partial response (PR) [n(%)] 69 (19.7) 86 (24.2)

MRD negativity rate (95% CI) c (%) 22.3 (18.0, 27.0) 6.2 (3.9, 9.2)

Odds ratio with 95% CId 4.36 (2.64, 7.21)p-valuee < 0.0001

D-VMP=daratumumab-bortezomib-melphalan-prednisone; VMP=bortezomib-melphalan-prednisone; MRD=minimalresidual disease; CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c Based on threshold of 10-5.d A Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. An odds ratio > 1 indicates anadvantage for D-VMP.e p-value from Fisherʼs exact test.

In responders, 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 durationof response had not been reached in the D-VMP group and was 21.3 months (range: 18.4, notestimable) in the VMP group.

A subgroup analysis was performed on patients at least 70 years old, or those 65-69 years old with

ECOG performance score of 2, or aged less than 65 years of age with significant comorbidity or

ECOG performance score of 2 (D-VMP: n=273, VMP: n=270). The efficacy results in this subgroupwere consistent with 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 theVMP group (VGPR rate:29%in D-VMP group and 26% in VMP group; CR: 22% in D-VMP group and 18% in VMP group; sCRrate: 20% in D-VMP group and 7% in VMP group). The safety results of this subgroup wereconsistent with the overall population. Furthermore, safety analysis of the subgroup of patients with an

ECOG performance score of 2 (D-VMP: n=89, VMP: n=84), was also consistent with the overallpopulation.

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

Study MMY3006 is a 2 part, open-label, randomised, active-controlled phase III study. Part 1compared induction and consolidation treatment with intravenous daratumumab 16 mg/kg incombination with bortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib,thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligiblefor ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when thepatient had recovered sufficiently, and engraftment was complete. In part 2, subjects with at least apartial response (PR) by day 100 post-transplant were re-randomised in a 1:1 ratio to daratumumabmaintenance or observation only. Only results from part 1 are described henceforth.

Bortezomib was administered by subcutaneous injection or intravenous injection at a dose of1.3 mg/m2 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 ASCT after cycle 4. Thalidomide was administered orally at 100 mg daily during the sixbortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on days 1, 2, 8, 9,15, 16, 22 and 23 of cycles 1 and 2, and at 40 mg on days 1-2 and 20 mg on 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 incycles 5 and 6. On the days of intravenous daratumumab infusion, the dexamethasone dose wasadministered intravenously as a pre-infusion medicinal product. Dose adjustments for bortezomib,thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

A total of 1085 patients were randomised: 543 to the D-VTd arm and 542 to the VTd arm. Thebaseline demographic and disease characteristics were similar between the two treatment groups. Themedian age was 58 (range: 22 to 65) years. All patients were ≤ 65 years: 43% were in the age group≥ 60-65 years, 41% were in the age group ≥ 50-60 years and 16% below age of 50 years. The majoritywere male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance scoreof 1 and 10% had an ECOG performance score of 2. Forty percent had International Staging System(ISS) stage I, 45% had ISS stage II and 15% had ISS stage III disease.

Efficacy was evaluated by the stringent complete response (sCR) rate at day 100 post-transplant and

PFS.

Table 17: Efficacy results from study MMY3006a

D-VTd (n=543) VTd (n=542) P valueb

Response assessment day 100 post-transplant

Stringent complete response (sCR) 157 (28.9%) 110 (20.3%) 0.0010

CR or better (sCR+CR) 211 (38.9%) 141 (26.0%) < 0.0001

Very good partial response or better(sCR+CR+VGPR) 453 (83.4%) 423 (78.0%)

MRD negativityc, d n(%) 346 (63.7%) 236 (43.5%) < 0.000195% CI (%) (59.5%, 67.8%) (39.3%, 47.8%)

Odds ratio with 95% CIe 2.27 (1.78, 2.90)

MRD negativity in combination with CR or 183 (33.7%) 108 (19.9%) < 0.0001betterc n(%)95% CI (%) (29.7%, 37.9%) (16.6%, 23.5%)

Odds ratio with 95% CIe 2.06 (1.56, 2.72)

D-VTd=daratumumab-bortezomib-thalidomide-dexamethasone; VTd=bortezomib-thalidomide-dexamethasone;

MRD=minimal residual disease; CI=confidence interval.a Based on intent-to-treat population.b p-value from Cochran Mantel-Haenszel Chi-Squared test.c Based on threshold of 10-5.d Regardless of response per IMWG.e Mantel-Haenszel estimate of the common odds ratio for stratified tables is used.

With a median follow-up of 18.8 months, the primary analysis of PFS by censoring patients who wererandomised to daratumumab maintenance in the second randomisation at the date of the secondrandomisation showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005. Results of an updated PFS analysiswith a median follow-up of 44.5 months, censoring patients who were randomised to daratumumabmaintenance in the second randomisation, showed 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.

Figure 8: Kaplan-Meier curve of PFS in study MMY3006

Relapsed/refractory multiple myeloma

The clinical efficacy and safety of intravenous daratumumab monotherapy for the treatment of adultpatients with relapsed and refractory multiple myeloma whose prior therapy included a proteasomeinhibitor and an immunomodulatory agent and who had demonstrated disease progression on the lasttherapy, was demonstrated in two open-label studies.

In study MMY2002, 106 patients with relapsed and refractory multiple myeloma received 16 mg/kgintravenous daratumumab until disease progression. The median patient age was 63.5 years (range, 31to 84 years), 11% of patients were ≥ 75 years of age, 49% were male and 79% were Caucasian.

Patients had received a median of 5 prior lines of therapy. Eighty percent of patients had received priorautologous stem cell transplantation (ASCT). Prior therapies included bortezomib (99%), lenalidomide(99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory tothe last line of treatment, 95% were refractory to both, a proteasome inhibitor (PI) andimmunomodulatory agent (IMiD), 77% were refractory to alkylating agents, 63% were refractory topomalidomide and 48% of patients were refractory to carfilzomib.

Efficacy results of the pre-planned interim analysis based on Independent Review Committee (IRC)assessment are presented in table 18 below.

Table 18: IRC assessed efficacy results for study MMY2002

Efficacy endpoint Intravenous daratumumab16 mg/kg

N=106

Overall response rate1 (ORR: sCR+CR+VGPR+PR) [n (%)] 31 (29.2)95% CI (%) (20.8, 38.9)

Stringent complete response (sCR) [n (%)] 3 (2.8)

Complete response (CR) [n] 0

Very good partial response (VGPR) [n (%)] 10 (9.4)

Partial response (PR) [n (%)] 18 (17.0)

Clinical benefit rate (ORR+MR) [n (%)] 36 (34.0)

Median duration of response [months (95% CI)] 7.4 (5.5, NE)

Median time to response [months (range)] 1 (0.9; 5.6)1 Primary efficacy endpoint (International Myeloma Working Group criteria).

CI=confidence interval; NE=not estimable; MR=minimal response.

Overall response rate (ORR) in MMY2002 was similar regardless of type of prior anti-myelomatherapy.

At a survival update with a median duration of follow-up of 14.7 months, median OS was 17.5 months(95% CI: 13.7, not estimable).

In study GEN501, 42 patients with relapsed and refractory multiple myeloma received 16 mg/kgintravenous daratumumab until disease progression. The median patient age was 64 years (range, 44 to76 years), 64% were male and 76% were Caucasian. Patients in the study had received a median of 4prior lines of therapy. Seventy-four percent of patients had received prior ASCT. Prior therapiesincluded bortezomib (100%), lenalidomide (95%), pomalidomide (36%) and carfilzomib (19%). Atbaseline, 76% of patients were refractory to the last line of treatment, 64% were refractory to both a PIand IMiD, 60% were refractory to alkylating agents, 36% were refractory to pomalidomide and 17%were refractory to carfilzomib.

Pre-planned interim analysis showed that treatment with daratumumab at 16 mg/kg led to a 36% ORRwith 5% CR and 5% VGPR. The median time to response was 1 (range: 0.5 to 3.2) month. Themedian duration of response was not reached (95% CI: 5.6 months, not estimable).

At a survival update with a median duration of follow-up 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, an open-label, randomised, active-controlled phase III study, compared treatmentwith intravenous daratumumab 16 mg/kg in combination with lenalidomide and low-dosedexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patientswith 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 givenwith low dose dexamethasone at 40 mg/week (or a reduced dose of 20 mg/week for patients > 75 yearsor BMI < 18.5). On intravenous daratumumab infusion days, 20 mg of the dexamethasone dose wasgiven as a pre-infusion medicinal product and the remainder given the day after the infusion.

Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 569 patients were randomised; 286 to the DRd arm and 283 to the Rd arm. The baselinedemographic and disease characteristics were similar between the intravenous daratumumab and thecontrol arm. The median patient age was 65 years (range 34 to 89 years) and 11% were ≥ 75 years.

The majority of patients (86%) received a prior PI, 55% of patients had received a prior IMiD,including 18% of patients who had received prior lenalidomide; and 44% of patients had received botha prior PI and IMiD. At baseline, 27% of patients were refractory to the last line of treatment. Eighteenpercent (18%) of patients 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 analysis of PFS in study MMY3003demonstrated an improvement in the DRd arm as compared to the Rd arm; the median PFS had notbeen 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). Results of an updated PFS analysis after a median follow-up of 55 months continued toshow an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFSwas 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), representing a 56% reduction in the risk of disease progression or death in patients treatedwith DRd (see figure 9).

Figure 9: Kaplan-Meier curve of PFS in study MMY3003

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

Figure 10: Kaplan-Meier curve of OS in study MMY3003

Additional efficacy results from study MMY3003 are presented in table 19 below.

Table 19: Additional efficacy results from study MMY3003

Response evaluable patient number DRd (n=281) Rd (n=276)

Overall response (sCR+CR+VGPR+PR) n(%) 261 (92.9) 211 (76.4)p-valuea < 0.0001

Stringent complete response (sCR) 51 (18.1) 20 (7.2)

Complete response (CR) 70 (24.9) 33 (12.0)

Very good partial response (VGPR) 92 (32.7) 69 (25.0)

Partial response (PR) 48 (17.1) 89 (32.2)

Median Time to Response [months (95% CI)] 1.0 (1.0, 1.1) 1.3 (1.1, 1.9)

Median Duration of Response [months (95% NE (NE, NE) 17.4 (17.4, NE)

CI)]

MRD negative rate (95% CI) b (%) 21.0 (16.4, 26.2) 2.8 (1.2, 5.5)

Odds ratio with 95% CIc 9.31 (4.31, 20.09)

P-valued < 0.0001

DRd=daratumumab-lenalidomide-dexamethasone; Rd=lenalidomide-dexamethasone; MRD=minimal residual disease;

CI=confidence interval; NE=not estimable.a p-value from Cochran Mantel-Haenszel Chi-Squared test.b Based on Intent-to-treat population and threshold of 10-5.c Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DRd.d p-value is from a Fisher’s exact test.

Combination treatment with bortezomib

Study MMY3004, an open-label, randomised, active-controlled phase III study, compared treatmentwith intravenous daratumumab 16 mg/kg in combination with bortezomib and dexamethasone (DVd),to treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiplemyeloma who had received at least one prior therapy. Bortezomib was administered by subcutaneousinjection or intravenous injection at a dose of 1.3 mg/m2 body surface area twice weekly for twoweeks (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 eachof the 8 bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or areduced dose of 20 mg/week for patients > 75 years, BMI < 18.5, poorly controlled diabetes mellitusor prior intolerance to steroid therapy. On the days of intravenous daratumumab infusion, 20 mg of thedexamethasone dose was administered as a pre-infusion medicinal product. intravenous daratumumabtreatment was continued until disease progression or unacceptable toxicity.

A total of 498 patients were randomised; 251 to the DVd arm and 247 to the Vd arm. The baselinedemographic and disease characteristics were similar between the intravenous daratumumab and thecontrol arm. The median patient age was 64 years (range 30 to 88 years) and 12% were ≥ 75 years.

Sixty-nine percent (69%) of patients had received a prior PI (66% received bortezomib) and 76% ofpatients received an IMiD (42% received lenalidomide). At baseline, 32% of patients were refractoryto 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 thestudy.

With a median follow-up of 7.4 months, the primary analysis of PFS in study MMY3004demonstrated an improvement in the DVd arm as compared to the Vd arm; the median PFS had notbeen 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). Results of an updated PFS analysis after a median follow-up of 50 monthscontinued 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), representing a 69% reduction in the risk of disease progression ordeath in patients treated with DVd versus Vd (see figure 11).

Figure 11: Kaplan-Meier curve of PFS in study MMY3004

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

Figure 12: Kaplan-Meier curve of OS in study MMY3004

Additional efficacy results from study MMY3004 are presented in table 20 below.

Table 20: Additional efficacy results from study MMY3004

Response evaluable patient number DVd (n=240) Vd (n=234)

Overall response (sCR+CR+VGPR+PR) n(%) 199 (82.9) 148 (63.2)

P-valuea < 0.0001

Stringent complete response (sCR) 11 (4.6) 5 (2.1)

Complete response (CR) 35 (14.6) 16 (6.8)

Very good partial response (VGPR) 96 (40.0) 47 (20.1)

Partial response (PR) 57 (23.8) 80 (34.2)

Median time to response [months (range)] 0.9 (0.8, 1.4) 1.6 (1.5, 2.1)

Median duration of response [months (95% CI)] NE (11.5, NE) 7.9 (6.7, 11.3)

MRD negative rate (95% CI)b 8.8% (5.6%, 13.0%) 1.2% (0.3%, 3.5%)

Odds ratio with 95% CIc 9.04 (2.53, 32.21)

P-valued 0.0001

DVd=daratumumab- bortezomib-dexamethasone; Vd=bortezomib-dexamethasone; MRD=minimal residual disease;

CI=confidence interval; NE=not estimable.a p-value from Cochran Mantel-Haenszel Chi-Squared test.b Based on Intent-to-treat population and threshold of 10-5.c Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio > 1 indicates an advantage for DVd.d p-value is from Fisher’s exact test.

Daratumumab as a large protein has a low likelihood of direct ion channel interactions. The effect ofdaratumumab on the QTc interval was evaluated in an open-label study for 83 patients (Study

GEN501) with relapsed and refractory multiple myeloma following daratumumab infusions (4 to24 mg/kg). Linear mixed PK-PD analyses indicated no large increase in mean QTcF interval (i.e.greater than 20 ms) at daratumumab Cmax.

The European Medicines Agency has waived the obligation to submit the results of studies with

DARZALEX in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).

In patients with multiple myeloma, daratumumab exposure in a monotherapy study following therecommended 1800 mg administration of DARZALEX subcutaneous formulation (weekly for8 weeks, biweekly for 16 weeks, monthly thereafter) as compared to 16 mg/kg intravenousdaratumumab for the same dosing schedule, showed non-inferiority for the co-primary endpoint ofmaximum Ctrough (cycle 3 day 1 pre-dose), with mean ± SD of 593 ± 306 µg/mL compared to522 ± 226 µg/mL for intravenous daratumumab, with a geometric mean ratio of 107.93% (90%

CI: 95.74-121.67).

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

Following the recommended dose of 1800 mg DARZALEX solution for subcutaneous injection, peakconcentrations (Cmax) increased 4.8-fold and total exposure (AUC0-7 days) increased 5.4-fold from firstdose to last weekly dose (8th dose). Highest trough concentrations for DARZALEX solution forsubcutaneous injection are typically observed at the end of the weekly dosing regimens for bothmonotherapy and combination therapy.

In patients with multiple myeloma, the simulated trough concentrations following 6 weekly doses of1800 mg DARZALEX solution for subcutaneous injection for combination therapy were similar to1800 mg DARZALEX solution for subcutaneous injection monotherapy.

In patients with newly diagnosed multiple myeloma eligible for ASCT, daratumumab exposure in acombination study with bortezomib, lenalidomide and dexamethasone (MMY3014) was similar to thatin monotherapy, with the maximum Ctrough (cycle 3 day 1 pre-dose) mean ± SD of 526±209 µg/mLfollowing the recommended 1800 mg administration of DARZALEX solution for subcutaneousinjection (weekly for 8 weeks, biweekly for 16 weeks, monthly thereafter).

In patients with newly diagnosed multiple myeloma for whom ASCT was not planned as initialtherapy or who were ineligible for ASCT, daratumumab exposure in a combination study withbortezomib, lenalidomide and dexamethasone (MMY3019) was similar to that in monotherapy andother combination therapies following similar dosing schedule, with the maximum Ctrough (cycle 3day 1 pre-dose) mean ± SD of 407 ± 183 µg/mL following the recommended 1800 mg administrationof DARZALEX solution for subcutaneous injection (weekly for 6 weeks, triweekly for 18 weeks,monthly thereafter).

In patients with multiple myeloma, daratumumab exposure in a combination study with pomalidomideand dexamethasone (study MMY3013) was similar to that in monotherapy, with the maximum Ctrough(cycle 3 day 1 pre-dose) mean ± SD of 537 ± 277 µg/mL following the recommended 1800 mgadministration of DARZALEX solution for subcutaneous injection (weekly for 8 weeks, biweekly for16 weeks, monthly thereafter).

At the recommended dose of 1800 mg in multiple myeloma patients, the absolute bioavailability of

DARZALEX solution for subcutaneous injection is 69%, with an absorption rate of 0.012 hour-1, withpeak concentrations occurring at 70 to 72 h (Tmax). At the recommended dose of 1800 mg in ALamyloidosis patients, the absolute bioavailability was not estimated, the absorption rate constant was0.77 day-1 (8.31% CV) and peak concentrations occurred at 3 days.

The model predicted mean estimate of the volume of distribution for the central compartment was5.25 L (36.9% CV) and peripheral compartment (V2) was 3.78 L in daratumumab monotherapy, andthe modeled mean estimate of the volume of distribution for V1 was 4.36 L (28.0% CV) and V2 was2.80 L when daratumumab was administered in combination with pomalidomide and dexamethasonein multiple myeloma patients. In AL amyloidosis patients, the model estimated apparent volume ofdistribution after subcutaneous administration is 10.8 L (3.1% CV). These results suggest thatdaratumumab is primarily localised to the vascular system with limited extravascular tissuedistribution.

Metabolism and elimination

Daratumumab exhibits both concentration and time-dependent pharmacokinetics with parallel linearand nonlinear (saturable) elimination that is characteristic of target-mediated clearance. Thepopulation PK model estimated mean clearance value of daratumumab is 4.96 mL/h (58.7% CV) indaratumumab monotherapy and 4.32 mL/h (43.5% CV) when daratumumab is administered incombination with pomalidomide and dexamethasone in multiple myeloma patients. In AL amyloidosispatients, the apparent clearance after subcutaneous administration is 210 mL/day (4.1% CV). Themodel-based geometric mean for half-life associated with linear elimination is 20.4 days (22.4% CV)in daratumumab monotherapy and 19.7 days (15.3% CV) when daratumumab was administered incombination with pomalidomide and dexamethasone in multiple myeloma patients and 27.5 days(74.0% CV) in AL amyloidosis patients. For the monotherapy and combination regimens, the steadystate is achieved at approximately 5 months into every 4 weeks dosage at the recommended dose andschedule (1800 mg; once weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeksthereafter).

A population PK analysis was conducted using data from DARZALEX solution for subcutaneousinjection monotherapy and combination therapy multiple myeloma studies, and the predicted PKexposures are summarised in table 21. Daratumumab exposures were similar between patients treatedwith DARZALEX solution for subcutaneous injection monotherapy and combination therapies.

Table 21: Daratumumab exposure following administration of DARZALEX subcutaneousformulation (1800 mg) or intravenous daratumumab (16 mg/kg) monotherapy inpatients with multiple myeloma

PK parameters Cycles subcutaneous intravenousdaratumumab daratumumab

Median (5th; 95th Median (5th; 95thpercentile) percentile)

Cycle 1, 1st weekly dose 123 (36; 220) 112 (43; 168)

Ctrough (µg/mL) Cycle 2, last weekly dose 563 (177; 1063) 472 (144; 809)(cycle 3 day 1 Ctrough)

Cycle 1, 1st weekly dose 132 (54; 228) 256 (173; 327)

Cmax (µg/mL)

Cycle 2, last weekly dose 592 (234; 1114) 688 (369; 1061)

Cycle 1, 1st weekly dose 720 (293; 1274) 1187 (773; 1619)

AUC0-7 days (µg/mL*day)

Cycle 2, last weekly dose 4017 (1515; 7564) 4019 (1740; 6370)

The predicted PK expsosures for 526 patients with transplant eligible multiple myeloma who received

DARZALEX solution for subcutaneous injection in combination with VRd are summarised intable 22.

Table 22: Daratumumab exposure following administration of DARZALEX subcutaneousformulation (1800 mg) in combination with VRd in patients with transplant eligiblemultiple myeloma

PK parameters Cycles subcutaneous daratumumab

Median (5th; 95th percentile)

Cycle 1, 1st weekly dose 113 (66; 171)

Ctrough (µg/mL) Cycle 2, last weekly dose (cycle 3 651 (413; 915)day 1 Ctrough)

Cycle 1, 1st weekly dose 117 (67; 179)

Cmax (µg/mL)

Cycle 2, last weekly dose 678 (431; 958)

Cycle 1, 1st weekly dose 643 (322; 1027)

AUC0-7 days (µg/mL*day)

Cycle 2, last weekly dose 4637 (2941; 6522)

A population PK analysis, using data from DARZALEX solution for subcutaneous injectioncombination therapy in AL amyloidosis patients, was conducted with data from 211 patients. At therecommended dose of 1800 mg, predicted daratumumab concentrations were slightly higher, butgenerally within the same range, in comparison with multiple myeloma patients.

Table 23: Daratumumab exposure following administration of DARZALEX subcutaneousformulation (1800 mg) in patients with AL amyloidosis

PK parameters Cycles subcutaneous daratumumab

Median (5th; 95th percentile)

Cycle 1, 1st weekly dose 138 (86; 195)

Ctrough (µg/mL) Cycle 2, last weekly dose 662 (315; 1037)(cycle 3 day 1 Ctrough)

Cycle 1, 1st weekly dose 151 (88; 226)

Cmax (µg/mL)

Cycle 2, last weekly dose 729 (390; 1105)

Cycle 1, 1st weekly dose 908 (482; 1365)

AUC0-7 days (µg/mL*day)

Cycle 2, last weekly dose 4855 (2562; 7522)

Age and gender

Based on population PK analyses in patients (33-92 years) receiving monotherapy or variouscombination therapies, age had no statistically significant effect on the PK of daratumumab. Noindividualisation is necessary for patients on the basis of age.

Gender had a statistically significant effect on PK parameters in patients with multiple myeloma butnot in patients with AL amyloidosis. Slightly higher exposure in females were observed than males,but the difference in exposure is not considered clinically meaningful. No individualisation isnecessary for patients on the basis of gender.

No formal studies of DARZALEX subcutaneous formulation in patients with renal impairment havebeen conducted. Population PK analyses were performed based on pre-existing renal function data inpatients with multiple myeloma receiving DARZALEX subcutaneous formulation monotherapy orvarious combination therapies in patients with multiple myeloma or AL amyloidosis. No clinicallyimportant differences in exposure to daratumumab were observed between patients with renalimpairment and those with normal renal function.

No formal studies of DARZALEX subcutaneous formulation in patients with hepatic impairment havebeen conducted.

Population PK analyses were performed in patients with multiple myeloma receiving DARZALEXsubcutaneous formulation monotherapy or various combination therapies in patients with multiplemyeloma and in AL amyloidosis. No clinically important differences in the exposure to daratumumabwere observed between patients with normal hepatic function and mild hepatic impairment. Therewere very few patients with moderate and severe hepatic impairment to make meaningful conclusionsfor these populations.

Based on the population PK analyses in patients receiving either DARZALEX subcutaneousformulation monotherapy or various combination therapies, the daratumumab exposure was similaracross races.

The flat-dose administration of DARZALEX subcutaneous formulation 1800 mg as monotherapyachieved adequate exposure for all body-weight subgroups. In patients with multiple myeloma, themean cycle 3 day 1 Ctrough in the lower body-weight subgroup (≤ 65 kg) was 60% higher and in thehigher body weight (> 85 kg) subgroup, 12% lower than the intravenous daratumumab subgroup. Insome patients with body weight > 120 kg, lower exposure was observed which may result in reducedefficacy. However, this observation is based on limited number of patients.

In patients with AL amyloidosis, no meaningful differences were observed in Ctrough across bodyweight.

Toxicology data have been derived from studies with daratumumab in chimpanzees and with asurrogate anti-CD38 antibody in cynomolgus monkeys. No chronic toxicity testing has beenconducted.

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

No animal studies have been performed to evaluate the potential effects of daratumumab onreproduction or development or to determine potential effects on fertility in males or females.

No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant humanhyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure ofhyaluronidase in monkeys given 22000 U/kg/week subcutaneously (12 times higher than the humandose) for 39 weeks. As hyaluronidase is a recombinant form of the endogenous human hyaluronidase,no carcinogenity, mutagenesis, or effects on fertility are expected.

Recombinant human hyaluronidase (rHuPH20)

L-histidine

L-histidine hydrochloride monohydrate

L-methionine

Polysorbate 20

Sorbitol (E420)

Water for injections

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

Unopened vial3 years.

During the shelf-life, the product in unpunctured vials may be stored at ambient temperature (≤ 30 °C)for a single period of up to 24 hours. Once the product has been taken out of the refrigerator, it mustnot be returned to the refrigerator (see section 6.6).

Prepared syringe

Chemical and physical in-use stability in syringe has been demonstrated for 24 hours at refrigeratedconditions (2 °C-8 °C), followed by no more than 12 hours at 15 °C-25 °C and ambient light. From amicrobiological point of view, unless the method of opening precludes the risk of microbialcontamination, the product should be used immediately. If not used immediately, in-use storage timesand conditions are the responsibility of the user.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

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

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

15 mL solution in a type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-offbutton containing 1800 mg of daratumumab. Pack size of 1 vial.

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

DARZALEX solution for subcutaneous injection should be a clear to opalescent and colourless toyellow solution. Do not use if opaque particles, discolouration or other foreign particles are present.

DARZALEX solution for subcutaneous injection is compatible with polypropylene or polyethylenesyringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusionsets; and stainless steel transfer and injection needles.

Remove the DARZALEX solution for subcutaneous injection vial from refrigerated storage(2 °C-8 °C) and equilibrate to ambient temperature (≤30 °C). The unpunctured vial may be stored atambient temperature and ambient light for a maximum of 24 hours in the original carton to protectfrom light. Keep out of direct sunlight. Do not shake.

Prepared syringe

Prepare the dosing syringe in controlled and validated aseptic conditions. Once transferred from thevial into the syringe, store DARZALEX solution for subcutaneous injection for up to 24 hoursrefrigerated followed by up to 12 hours at 15 °C-25 °C and ambient light (see section 6.3). If stored inthe refrigerator, allow the solution to reach ambient temperature before administration.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/16/1101/004

Date of first authorisation: 20 May 2016

Date of latest renewal: 06 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.