Daratumumab and Hyaluronidase-fihj (human Recombinant)

INDICATIONS AND USAGE DARZALEX FASPRO is a combination of daratumumab, a CD38-directed cytolytic antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of adult patients with: multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant multiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor multiple myeloma in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy multiple myeloma as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent high-risk smoldering multiple myeloma as monotherapy light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide and dexamethasone in newly diagnosed patients. Limitations of Use: DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials ( 1.3 ) 1.1 Multiple Myeloma DARZALEX FASPRO is indicated for the treatment of adult patients with [see Clinical Studies (14) ] : multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant. multiple myeloma in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy. multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. multiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor. multiple myeloma in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. multiple myeloma as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. 1.2 High-Risk Smoldering Multiple Myeloma DARZALEX FASPRO as monotherapy is indicated for the treatment of adult patients with high-risk smoldering multiple myeloma. 1.3 Light Chain Amyloidosis DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. Limitations of Use DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials [see Warnings and Precautions (5.2) ] .

DOSAGE AND ADMINISTRATION For subcutaneous use only. Pre-medicate with a corticosteroid, acetaminophen and a histamine-1 receptor antagonist. ( 2.6 ) The recommended dosage of DARZALEX FASPRO is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3 to 5 minutes according to recommended schedule. ( 2.2 , 2.3 , 2.4 ) Administer post-medications as recommended. ( 2.6 ) 2.1 Important Dosing Information DARZALEX FASPRO is for subcutaneous use only. Administer medications before and after administration of DARZALEX FASPRO to minimize administration-related reactions [see Dosage and Administration (2.6) ] . Type and screen patients prior to starting DARZALEX FASPRO. 2.2 Recommended Dosage for Multiple Myeloma The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Tables 1, 2, 3, 4, 5, and 6 provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of a combination therapy. Monotherapy and In Combination with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd), Pomalidomide and Dexamethasone (DARZALEX FASPRO-Pd) or Carfilzomib and Dexamethasone (DARZALEX FASPRO-Kd) Use the dosing schedule provided in Table 1 when DARZALEX FASPRO is administered: in combination with lenalidomide and dexamethasone (4-week cycle) OR in combination with pomalidomide and dexamethasone (4-week cycle) OR in combination with carfilzomib and dexamethasone (4-week cycle) OR as monotherapy. Table 1: DARZALEX FASPRO dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) and for monotherapy Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) Use the dosing schedule provided in Table 2 when DARZALEX FASPRO is administered in combination with bortezomib, melphalan and prednisone (6-week cycle). Table 2: DARZALEX FASPRO dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 54 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 16 doses) Week 55 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 55 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Thalidomide, and Dexamethasone (DARZALEX FASPRO-VTd) Use the dosing schedule in Table 3 when DARZALEX FASPRO is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle). Table 3: DARZALEX FASPRO dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Eligible for Autologous Stem Cell Transplant (ASCT) Use the dosing schedule in Table 4 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT. Table 4: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (4-week cycle) Treatment phase Weeks Schedule Induction Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 16 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 4 doses) Stop for high dose chemotherapy and ASCT Consolidation Weeks 1 to 8 First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT every two weeks (total of 4 doses) When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib, Lenalidomide, and Dexamethasone (DARZALEX FASPRO-VRd) for Patients Who Are Ineligible for ASCT Use the dosing schedule in Table 5 when DARZALEX FASPRO is administered in combination with bortezomib, lenalidomide, and dexamethasone (3-week cycle) for treatment of newly diagnosed multiple myeloma patients who are ineligible for ASCT. Table 5: DARZALEX FASPRO dosing schedule in combination with bortezomib, lenalidomide and dexamethasone (3-week cycle) Weeks Schedule Weeks 1 to 6 weekly (total of 6 doses) Weeks 7 to 24 First dose of the every-3-week dosing schedule is given at Week 7 every three weeks (total of 6 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs. In Combination with Bortezomib and Dexamethasone (DARZALEX FASPRO-Vd) Use the dosing schedule in Table 6 when DARZALEX FASPRO is administered in combination with bortezomib and dexamethasone (3-week cycle). Table 6: DARZALEX FASPRO dosing schedule in combination with bortezomib and dexamethasone (3-week cycle) Weeks Schedule Weeks 1 to 9 weekly (total of 9 doses) Weeks 10 to 24 First dose of the every-3-week dosing schedule is given at Week 10 every three weeks (total of 5 doses) Week 25 onwards until disease progression First dose of the every-4-week dosing schedule is given at Week 25 every four weeks When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. 2.3 Recommended Dosage for High-Risk Smoldering Multiple Myeloma The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Use the dosing schedule provided in Table 7 when DARZALEX FASPRO is administered as monotherapy in high-risk smoldering multiple myeloma patients (4-week cycle). Table 7: DARZALEX FASPRO dosing schedule for monotherapy (4-week cycle) Weeks Schedule Weeks 1 to 8 weekly (total of 8 doses) Weeks 9 to 24 First dose of the every-2-week dosing schedule is given at Week 9 every two weeks (total of 8 doses) Week 25 onwards until diagnosis of multiple myeloma or a maximum of 3 years First dose of the every-4-week dosing schedule is given at Week 25 every four weeks 2.4 Recommended Dosage for Light Chain Amyloidosis In Combination with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO-VCd) The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes. Use the dosing schedule provided in Table 8 when DARZALEX FASPRO is adm

WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions : Permanently discontinue DARZALEX FASPRO for life-threatening reactions. ( 5.1 ) Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis : Monitor patients with cardiac involvement more frequently for cardiac adverse reactions and administer supportive care as appropriate. ( 5.2 ) Infections : DARZALEX FASPRO can cause serious and fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.3 ) Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO to allow recovery of neutrophils. ( 5.4 ) Thrombocytopenia : Monitor complete blood cell counts periodically during treatment. Consider withholding DARZALEX FASPRO to allow recovery of platelets. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception. ( 5.6 , 8.1 , 8.3 ) Interference with cross-matching and red blood cell antibody screening : Type and screen patients prior to starting treatment. Inform blood banks that a patient has received DARZALEX FASPRO. ( 5.7 , 7.1 ) 5.1 Hypersensitivity and Other Administration Reactions Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO [see Adverse Reactions (6.2) ] . Systemic Reactions In a pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3%, Grade 3: 0.8%, Grade 4: 0.1%). In patients with high-risk smoldering multiple myeloma (N=193), systemic administration-related reactions occurred in 17% of patients in AQUILA (Grade 2: 7%, Grade 3: 1%). In all patients (N=1639), systemic administration-related reactions occurred in 7% of patients with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 283 systemic administration-related reactions that occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients. Severe reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision. Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids [see Dosage and Administration (2.6) ] . Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions [see Dosage and Administration (2.6) ] . Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO. Local Reactions In this pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N=193), injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 1.1%. The most frequent (>1%) injection-site reactions were injection site erythema and injection site rash. In patients with high-risk smoldering multiple myeloma (N=193), injection-site reactions occurred in 28% of patients, including Grade 2 reactions in 3%. These local reactions occurred a median of 6 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management. 5.2 Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions (6.1) ] . Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate. 5.3 Infections DARZALEX FASPRO can cause serious, life-threatening, or fatal infections. In patients who received DARZALEX FASPRO in a pooled safety population including patients with smoldering multiple myeloma and light chain (AL) amyloidosis (N=1639), serious infections, including opportunistic infections, occurred in 24% of patients, Grade 3 or 4 infections occurred in 22%, and fatal infections occurred in 2.5%. The most common type of serious infection reported was pneumonia (8.5%). Monitor patients for signs and symptoms of infection prior to and during treatment with DARZALEX FASPRO and treat appropriately. Administer prophylactic antimicrobials according to guidelines [see Dosage and Administration (2.6) ] . 5.4 Neutropenia Daratumumab may increase neutropenia induced by background therapy [see Adverse Reactions (6.1) ] . Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3–4 neutropenia were observed. 5.5 Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1) ] . Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets. 5.6 Embryo-Fetal Toxicity Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . The combination of DARZALEX FASPRO with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use

CONTRAINDICATIONS DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ]. Patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation. ( 4 )

DRUG INTERACTIONS 7.1 Effects of Daratumumab on Laboratory Tests Interference with Indirect Antiglobulin Tests (Indirect Coombs Test) Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References (15) ] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices. 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). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO-treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity and Other Administration Reactions [see Warnings and Precautions (5.1) ] . Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis [see Warnings and Precautions (5.2) ] . Infections [see Warnings and Precautions (5.3) ] . Neutropenia [see Warnings and Precautions (5.4) ] . Thrombocytopenia [see Warnings and Precautions (5.5) ] . The most common adverse reactions (≥20%) in patients with multiple myeloma eligible for autologous stem cell transplant who received DARZALEX FASPRO-VRd are peripheral neuropathy, fatigue, upper respiratory infection, constipation, musculoskeletal pain, insomnia, rash, diarrhea, edema, and pyrexia. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who were ineligible for autologous stem cell transplant who received DARZALEX FASPRO-VRd are upper respiratory tract infection, sensory neuropathy, musculoskeletal pain, diarrhea, fatigue, edema, rash, motor dysfunction, COVID-19, constipation, sleep disorder, cough, pneumonia, renal impairment, dizziness, nausea, urinary tract infection, pyrexia, abdominal pain, dyspnea, decreased appetite, and bruising. ( 6.1 ) The most common adverse reaction (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO monotherapy is upper respiratory tract infection. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-Pd are fatigue, pneumonia, upper respiratory tract infection, and diarrhea. ( 6.1 ) The most common adverse reactions (≥20%) in patients with multiple myeloma who received DARZALEX FASPRO-Kd are upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral. ( 6.1 ) The most common adverse reactions (≥20%) in patients with high-risk smoldering multiple myeloma who received DARZALEX FASPRO monotherapy are upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions. ( 6.1 ) The most common adverse reactions (≥20%) in patients with light chain (AL) amyloidosis are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough. ( 6.1 ) The most common (≥40%) hematology laboratory abnormalities with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone (n=351) from the start of induction to the end of consolidation compared to bortezomib, lenalidomide and dexamethasone (VRd) (n=347) was evaluated in PERSEUS [see Clinical Studies (14.1) ] . Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8 and once every 2 weeks from weeks 9 to 16 during induction in combination with VRd or VRd alone. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT. Within 12 weeks of ASCT, and when engraftment was complete, patients received DARZALEX FASPRO once every 2 weeks from weeks 1 to 8 during consolidation in combination with VRd or VRd alone. The median duration of treatment for induction and consolidation was 9.9 months (0.5 to 18.5 months) for DARZALEX FASPRO-VRd. Serious adverse reactions occurred in 37% of patients who received DARZALEX FASPRO-VRd. The most frequent serious adverse reaction in >5% of patients who received DARZALEX FASPRO-VRd was pneumonia (6%). Fatal adverse reactions occurred in 1.7% of patients who received DARZALEX FASPRO-VRd. Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO-VRd. An adverse reaction which resulted in permanent discontinuation of DARZALEX FASPRO-VRd in more than 1 patient included sepsis. The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, upper respiratory infection, constipation, musculoskeletal pain, insomnia, rash, diarrhea, edema, and pyrexia. Table 9 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PERSEUS. Table 9: Adverse Reactions (≥10%) in Patients Who Received DARZALEX FASPRO-VRd through the End of Consolidation in PERSEUS Adverse Reaction DARZALEX FASPRO-VRd (N=351) VRd (N=347) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Key: VRd=bortezomib-lenalidomide-dexamethasone Nervous system disorders Peripheral neuropathy Peripheral neuropathy includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. 52 5 54 4 Paresthesia 11 <1 Only Grade 3 adverse reactions occurred. 11 <1 General disorders and administration site conditions Fatigue Includes other related terms. 35 3 37 5 Edema 22 1 21 1 Pyrexia 21 2 22 3 Infections Upper respiratory tract infection Upper respiratory tract infection includes fungal pharyngitis, h1n1 influenza, influenza, influenza like illness, laryngitis, nasopharyngitis, oral candidiasis, oropharyngeal candidiasis, parainfluenzae virus infection, pharyngitis, respiratory moniliasis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, upper respiratory tract infection, viral tonsillitis, and viral upper respiratory tract infection. 32 1 26 2 Pneumonia Pneumonia includes bronchopulmonary aspergillosis, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, and pneumonia streptococcal. 14 9 10 6 Fatal adverse reactions included Pneumonia: n=1 (0.3%) in the VRd arm. Gastrointestinal disorders Constipation 31 2 30 2 Diarrhea 23 3 25 5 Nausea 16 1 12 1 Abdominal pain 11 0 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 26 1 23 1 Muscle spasm 12 0 9 <1 Psychiatric disorders Insomnia 26 2 16 2 Skin and subcutaneous tissue disorders Rash 25 3 31 5 Hepatobiliary disorders Hepatotoxicity Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic cytolysis, hepatic failure, hepatic function abnormal, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, and liver disorder 16 6 16 5 Respiratory, thoracic and mediastinal disorders Cough 12 <1 8 0 Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, lenalidomide and dexamethasone include: Gastrointestinal disorders: vomiting, hemorrhoids Musculoskeletal and connective tissue diso

Mechanism of Action CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including clonal plasma cells in multiple myeloma and light chain (AL) amyloidosis, as well as other cell types. Surface CD38 has multiple functions, including receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+T regs ) and B cells (CD38+B regs ) are decreased by daratumumab. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in DARZALEX FASPRO acts locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.