Darzalex Faspro Drug Information
Generic name: DARATUMUMAB AND HYALURONIDASE-FIHJ (HUMAN RECOMBINANT)
CD38-directed Cytolytic Antibody [EPC] Endoglycosidase [EPC]
Uses of Darzalex Faspro
Multiple Myeloma DARZALEX FASPRO is 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 DARZALEX
FASPRO as monotherapy is indicated for the treatment of adult patients with high-risk smoldering multiple myeloma.
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.
Dosage & Administration of Darzalex Faspro
Important Dosing Information DARZALEX FASPRO is for subcutaneous use only. Administer medications before and after administration of DARZALEX FASPRO to minimize administration-related reactions. Tables 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 When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies 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) When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies 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). 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.
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.
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). Use the dosing schedule provided in Table 8 when DARZALEX FASPRO is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).
Missed DARZALEX FASPRO Doses If a dose of DARZALEX FASPRO is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.
Recommended Concomitant Medications Pre-medication Administer the following pre-medications 1 to 3 hours before each dose of DARZALEX FASPRO: Acetaminophen 650 mg to 1,000 mg orally Diphenhydramine 25 mg to 50 mg (or equivalent) orally or intravenously Corticosteroid (long- or intermediate-acting) Monotherapy Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO. In Combination Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO administration.
When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX FASPRO administration days. Do not administer background regimen-specific corticosteroids (e.g., prednisone) on DARZALEX FASPRO administration days when patients have received dexamethasone (or equivalent) as a pre-medication. Post-medication Administer the following post-medications: Monotherapy Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX FASPRO.
In Combination Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) on the day after administration of DARZALEX FASPRO. If a background regimen-specific corticosteroid (e.g., dexamethasone, prednisone) is administered the day after the administration of DARZALEX FASPRO, additional corticosteroids may not be needed. If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).
For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 doses of DARZALEX FASPRO, consider discontinuing these additional post-medications, if the patient does not experience a major systemic administration-related reaction. Prophylaxis for Herpes Zoster Reactivation Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX FASPRO and continue for 3 months following the end of treatment.
Dosage Modifications for Adverse Reactions
No dose reductions of DARZALEX FASPRO are recommended. Consider withholding DARZALEX FASPRO to allow recovery of blood cell counts in the event of myelosuppression.
Preparation and Administration DARZALEX FASPRO should be administered by a healthcare provider. To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DARZALEX FASPRO for subcutaneous use. Do not administer DARZALEX FASPRO intravenously.
DARZALEX FASPRO is ready to use. Preparation Remove the DARZALEX FASPRO vial from refrigerated storage and equilibrate to ambient temperature. Store the unpunctured vial at ambient temperature and ambient light for a maximum of 24 hours.
Keep out of direct sunlight. Do not shake. Withdraw 15 mL from the vial into a syringe using an 18G to 22G transfer needle with a regular bevel.
Insert the needle into the vial at a 90° angle within the ring of the stopper. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present.
DARZALEX FASPRO is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately. After the solution of DARZALEX FASPRO is withdrawn into the syringe, replace the transfer needle with a syringe closing cap.
Label the syringe appropriately to include the route of administration per institutional standards. Label the syringe with the peel-off label. To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.
Storage If the syringe containing DARZALEX FASPRO is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours and/or at room temperature at 15°C to 25°C (59°F to 77°F) for up to 12 hours under ambient light. Discard if storage time exceeds these limits. If stored in the refrigerator, allow the solution to come to room temperature before administration.
No data are available on performing the injection at other sites of the body. Rotate injection sites for successive injections. Never inject DARZALEX FASPRO into areas where the skin is red, 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 by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose. During treatment with DARZALEX FASPRO, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO.
| 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 |
| 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 |
| 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) |
| 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) |
| 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 |
| 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 |
| 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 |
| 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 or a maximum of 2 years First dose of the every-4-week dosing schedule is given at Week 25 | every four weeks |
Side Effects of Darzalex Faspro
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. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT.
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 10: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline in Patients Who Received DARZALEX FASPRO-VRd through the End of Consolidation in PERSEUS 3 Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide and dexamethasone compared to bortezomib, lenalidomide and dexamethasone (VRd) was evaluated in CEPHEUS in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial therapy.
Fatal adverse reactions occurred in 16.8% of patients who received DARZALEX FASPRO-VRd. Table 11 summarized the adverse reactions in patients who received DARZALEX FASPRO in CEPHEUS. Table 12: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline in Patients Who Received DARZALEX FASPRO- 5 Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant In Combination with Bortezomib, Melphalan and Prednisone The safety of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES.
Among these patients, 93% were exposed for 6 months or longer and 19% were exposed for greater than one year. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.
Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient was neutropenic sepsis. Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO.
Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia. The most common adverse reactions (≥20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. Table 13 summarizes the adverse reactions in patients who received DARZALEX FASPRO in PLEIADES.
Table 14: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO-VMP) in PLEIADES Relapsed/Refractory Multiple Myeloma In Combination with Lenalidomide and Dexamethasone The safety of DARZALEX FASPRO with lenalidomide and dexamethasone was evaluated in a single-arm cohort of PLEIADES. Among these patients, 92% were exposed for 6 months or longer and 20% were exposed for greater than one year. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient were pneumonia and anemia.
Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased. The most common adverse reactions (≥20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea. Table 16: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Lenalidomide and Dexamethasone (DARZALEX FASPRO-Rd) in PLEIADES 8 In Combination with Pomalidomide and Dexamethasone The safety of DARZALEX FASPRO with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone (Pd) in patients who had received at least one prior line of therapy with lenalidomide and a proteasome inhibitor (PI) was evaluated in APOLLO.
Among patients receiving DARZALEX FASPRO-Pd, 71% were exposed for 6 months or longer and 50% were exposed for greater than one year. Serious adverse reactions occurred in 50% of patients who received DARZALEX FASPRO-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO-Pd were pneumonia (15%) and lower respiratory tract infection (12%).
Table 17 summarizes the adverse reactions in patients who received DARZALEX FASPRO in APOLLO. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year. Serious adverse reactions occurred in 27% of patients who received DARZALEX FASPRO in combination with carfilzomib and dexamethasone.
The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral. Table 20: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO-Kd in PLEIADES 5 Monotherapy The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA. Among patients receiving DARZALEX FASPRO, 37% were exposed for 6 months or longer and 1% were exposed for greater than one year.
Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than 1 patient were general physical health deterioration, septic shock, and respiratory failure. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 2 patients were thrombocytopenia and hypercalcemia.
The most common adverse reaction (≥20%) was upper respiratory tract infection. Table 21 summarizes the adverse reactions in COLUMBA. Table 22: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO or High-Risk Smoldering Multiple Myeloma The safety of DARZALEX FASPRO as monotherapy in patients with high-risk smoldering multiple myeloma was evaluated in AQUILA.
The median duration of treatment for patients receiving DARZALEX FASPRO was 35 months (0 to 36 months). Adverse reactions which resulted in permanent discontinuation of DARZALEX FASPRO in more than 1 patient included fatigue, anxiety, and dyspnea. Adverse reactions which required dosage interruption in ≥5% of patients included upper respiratory infection, pneumonia, and COVID-19.
The most common adverse reactions (≥20%) were upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions. Table 23 summarizes the adverse reactions in patients who received DARZALEX FASPRO in AQUILA. Table 24: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with High-Risk Smoldering Multiple Myeloma Who Received DARZALEX FASPRO in AQUILA 1 Light Chain Amyloidosis In Combination with Bortezomib, Cyclophosphamide and Dexamethasone The safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (DARZALEX FASPRO-VCd) was evaluated in ANDROMEDA.
Among patients who received DARZALEX FASPRO-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year. Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Fatal adverse reactions occurred in 11% of patients.
Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure. Table 25 below summarizes the adverse reactions in patients who received DARZALEX FASPRO in ANDROMEDA. Table 26: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO with Bortezomib, Cyclophosphamide and Dexamethasone s in Light Chain (AL) Amyloidosis Among patients who received DARZALEX FASPRO in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3%), Stage II (46%) and Stage III (51%).
Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage I and II and 28% of patients with Stage III). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage I and II and 19% of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the DARZALEX FASPRO-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).
Postmarketing Experience
The following adverse reactions have been identified with post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System: Anaphylactic reaction, Systemic administration reactions (including death) Gastrointestinal: Pancreatitis Infections: Cytomegalovirus, Listeriosis
| 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 |
| Laboratory Abnormality | DARZALEX FASPRO-VRd Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=351 for DARZALEX FASPRO-VRd and N=346 for VRd. | VRd | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Key: VRd=bortezomib-lenalidomide-dexamethasone | ||||
| Hematology | ||||
| Decreased platelets | 89 | 34 | 78 | 25 |
| Decreased lymphocytes | 87 | 69 | 69 | 43 |
| Decreased leukocytes | 78 | 47 | 56 | 22 |
| Decreased neutrophils | 67 | 52 | 47 | 34 |
| Decreased hemoglobin | 39 | 7 | 43 | 6 |
| Chemistry | ||||
| Increased alanine aminotransferase (ALT) | 52 | 7 | 48 | 5 |
| Decreased sodium | 40 | 5 | 25 | 5 |
| Increased alkaline phosphatase | 39 | 0 | 36 | 1 |
| Decreased potassium | 30 | 6 | 24 | 3 |
| Adverse Reaction | DARZALEX FASPRO-VRd (N=197) | VRd (N=195) | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Key: VRd=bortezomib-lenalidomide dexamethasone | ||||
| Infections | ||||
| Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, influenza, influenza like illness, laryngitis, nasal congestion, nasopharyngitis, parainfluenzae virus infection, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection bacterial, respiratory tract infection viral, rhinitis, rhinovirus infection, sinus congestion, sinus disorder, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract inflammation, and viral upper respiratory tract infection. | 75 | 4 Only Grade 3 adverse reactions occurred. | 63 | 3 |
| COVID-19 Includes other related terms. | 39 Fatal adverse reactions occurred for Abdominal pain: n=1 (1%) in the DARZALEX FASPRO-VRd arm; COVID-19: n=7 (4%) in the DARZALEX FASPRO-VRd arm and n=5 (3%) in the VRd arm; Pneumonia: n=8 (4%) in the DARZALEX FASPRO-VRd arm and n=5 (3%) in the VRd arm; Dyspnea: n=1 (1%) in the DARZALEX FASPRO-VRd arm. | 9 | 25 | 3 |
| Pneumonia Pneumonia includes bronchopulmonary aspergillosis, covid-19 pneumonia, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia cryptococcal, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia viral, and tuberculosis. | 31 | 16 | 26 | 15 |
| Urinary tract infection | 24 | 4 | 17 | 3 |
| Nervous system disorders | ||||
| Sensory neuropathy Sensory neuropathy includes anosmia, burning sensation, dysesthesia, hyperesthesia, hyperesthesia teeth, hypoesthesia, hypoesthesia oral, neuralgia, neuropathy peripheral, oral dysesthesia, palmar-plantar erythrodysesthesia syndrome, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, and skin burning sensation. | 72 | 12 | 72 | 10 |
| Motor dysfunction Motor dysfunction includes balance disorder, essential tremor, extrapyramidal disorder, facial paralysis, gait disturbance, hypotonia, mobility decreased, motor dysfunction, muscle contractions involuntary, muscle contracture, muscle spasms, muscular weakness, myopathy, paraparesis, peripheral motor neuropathy, peroneal nerve palsy, pharyngeal paresthesia, and tremor. | 44 | 11 | 37 | 7 |
| Dizziness | 26 | 2 | 26 | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain | 62 | 9 | 61 | 7 |
| Gastrointestinal disorders | ||||
| Diarrhea | 57 | 12 | 59 | 9 |
| Constipation | 38 | 2 | 42 | 3 |
| Nausea | 25 | 0 | 25 | 2 |
| Abdominal pain | 23 | 1 | 17 | 2 |
| General disorders and administration site conditions | ||||
| Fatigue | 56 | 14 | 53 | 11 |
| Edema | 54 | 4 | 46 | 2 |
| Pyrexia | 24 | 1 | 16 | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Rash | 50 | 8 | 47 | 7 |
| Psychiatric disorders | ||||
| Sleep disorder | 33 | 3 | 33 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 32 | 1 | 21 | 1 |
| Dyspnea | 21 | 2 | 17 | 1 |
| Renal and urinary disorders | ||||
| Renal impairment Renal impairment includes acute kidney injury, blood creatinine increased, chronic kidney disease, creatinine renal clearance decreased, glomerular filtration rate decreased, prerenal failure, renal failure, renal impairment, and renal injury. | 26 | 7 | 25 | 6 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 21 | 1 | 20 | 3 |
| Injury, poisoning and procedural complications | ||||
| Bruising | 20 | 0 | 12 | 0 |
| Laboratory Abnormality | DARZALEX FASPRO-VRd Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=197 for DARZALEX FASPRO-VRd and N=194 for VRd. | VRd | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Key: VRd=bortezomib-lenalidomide-dexamethasone | ||||
| Hematology | ||||
| Decreased leukocytes | 93 | 39 | 77 | 15 |
| Decreased neutrophils | 89 | 49 | 75 | 35 |
| Decreased lymphocytes | 87 | 55 | 72 | 38 |
| Decreased platelets | 81 | 31 | 73 | 23 |
| Decreased hemoglobin | 53 | 14 | 52 | 16 |
| Chemistry | ||||
| Increased alanine aminotransferase (ALT) | 66 | 7 | 61 | 3 |
| Increased creatinine | 54 | 5 | 56 | 3 |
| Decreased potassium | 53 | 19 | 36 | 12 |
| Decreased sodium | 48 | 16 | 40 | 13 |
| Increased aspartate aminotransferase (AST) | 43 | 3 | 46 | 3 |
| Increased alkaline phosphatase | 43 | 2 | 31 | 1 |
| Decreased corrected calcium | 32 | 5 | 26 | 5 |
| Adverse Reaction | DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone (N=67) | |
|---|---|---|
| All Grades (%) | Grades ≥3 (%) | |
| Infections | ||
| Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. | 39 | 0 |
| Bronchitis | 16 | 0 |
| Pneumonia Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial. | 15 | 7 Only Grade 3 adverse reactions occurred. |
| Gastrointestinal disorders | ||
| Constipation | 37 | 0 |
| Nausea | 36 | 0 |
| Diarrhea | 33 | 3 |
| Vomiting | 21 | 0 |
| Abdominal pain Abdominal pain includes abdominal pain, and abdominal pain upper. | 13 | 0 |
| General disorders and administration site conditions | ||
| Fatigue Fatigue includes asthenia, and fatigue. | 36 | 3 |
| Pyrexia | 34 | 0 |
| Edema peripheral Edema peripheral includes edema, edema peripheral, and peripheral swelling. | 13 | 1 |
| Nervous system disorders | ||
| Peripheral sensory neuropathy | 34 | 1 |
| Dizziness | 10 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough Cough includes cough, and productive cough. | 24 | 0 |
| Psychiatric disorders | ||
| Insomnia | 22 | 3 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 21 | 3 |
| Musculoskeletal chest pain | 12 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 15 | 1 |
| Skin and subcutaneous tissue disorders | ||
| Rash | 13 | 0 |
| Pruritus | 12 | 0 |
| Vascular disorders | ||
| Hypertension | 13 | 6 |
| Hypotension | 10 | 3 |
| Laboratory Abnormality | DARZALEX FASPRO with Bortezomib, Melphalan and Prednisone Denominator is based on the safety population treated with DARZALEX FASPRO-VMP (N=67). | |
|---|---|---|
| All Grades (%) | Grades 3–4 (%) | |
| Decreased leukocytes | 96 | 52 |
| Decreased lymphocytes | 93 | 84 |
| Decreased platelets | 93 | 42 |
| Decreased neutrophils | 88 | 49 |
| Decreased hemoglobin | 48 | 19 |
| Adverse Reaction | DARZALEX FASPRO with Lenalidomide and Dexamethasone (N=65) | |
|---|---|---|
| All Grades (%) | Grades ≥3 (%) | |
| General disorders and administration site conditions | ||
| Fatigue Fatigue includes asthenia, and fatigue. | 52 | 5 Only Grade 3 adverse reactions occurred. |
| Pyrexia | 23 | 2 |
| Edema peripheral | 18 | 3 |
| Gastrointestinal disorders | ||
| Diarrhea | 45 | 5 |
| Constipation | 26 | 2 |
| Nausea | 12 | 0 |
| Vomiting | 11 | 0 |
| Infections | ||
| Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. | 43 | 3 |
| Pneumonia Pneumonia includes lower respiratory tract infection, lung infection, and pneumonia. | 23 | 17 |
| Bronchitis Bronchitis includes bronchitis, and bronchitis viral. | 14 | 2 |
| Urinary tract infection | 11 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Muscle spasms | 31 | 2 |
| Back pain | 14 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. | 22 | 3 |
| Cough Cough includes cough, and productive cough. | 14 | 0 |
| Nervous system disorders | ||
| Peripheral sensory neuropathy | 17 | 2 |
| Psychiatric disorders | ||
| Insomnia | 17 | 5 |
| Metabolism and nutrition disorders | ||
| Hyperglycemia | 12 | 9 |
| Hypocalcemia | 11 | 0 |
| Laboratory Abnormality | DARZALEX FASPRO with Lenalidomide and Dexamethasone Denominator is based on the safety population treated with DARZALEX FASPRO-Rd (N=65). | |
|---|---|---|
| All Grades (%) | Grades 3–4 (%) | |
| Decreased leukocytes | 94 | 34 |
| Decreased lymphocytes | 82 | 58 |
| Decreased platelets | 86 | 9 |
| Decreased neutrophils | 89 | 52 |
| Decreased hemoglobin | 45 | 8 |
| Adverse Reaction | DARZALEX FASPRO-Pd (N=149) | Pd (N=150) | ||
|---|---|---|---|---|
| All Grades (%) | Grades ≥3 (%) | All Grades (%) | Grades ≥3 (%) | |
| Key: Pd=pomalidomide-dexamethasone | ||||
| General disorders and administration site conditions | ||||
| Fatigue Fatigue includes asthenia, and fatigue. | 46 | 13 | 39 | 5 Only Grade 3 adverse reactions occurred. |
| Pyrexia | 19 | 0 | 14 | 0 |
| Edema peripheral Edema peripheral includes edema, edema peripheral and peripheral swelling. | 15 | 0 | 9 | 0 |
| Infections | ||||
| Pneumonia Pneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. | 38 | 23 Grade 5 adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO-Pd arm and n=2 (1.3%) in the Pd arm. | 27 | 17 |
| Upper respiratory infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection. | 36 | 1 | 22 | 2 |
| Gastrointestinal disorders | ||||
| Diarrhea | 22 | 5 | 14 | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough Cough includes cough, and productive cough. | 13 | 0 | 8 | 0 |
| Laboratory Abnormality | DARZALEX FASPRO-Pd Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=148 for DARZALEX FASPRO-Pd and N=149 for Pd. | Pd | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Key: Pd=pomalidomide-dexamethasone | ||||
| Decreased neutrophils | 97 | 84 | 84 | 63 |
| Decreased leukocytes | 95 | 64 | 82 | 40 |
| Decreased lymphocytes | 93 | 59 | 79 | 33 |
| Decreased platelets | 75 | 19 | 60 | 19 |
| Decreased hemoglobin | 51 | 16 | 57 | 15 |
| Adverse Reaction | DARZALEX FASPRO-Kd (N=66) | |
|---|---|---|
| All Grades (%) | Grade ≥3 (%) | |
| Infections and infestations | ||
| Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. | 52 | 0 |
| Bronchitis Bronchitis includes bronchitis, and bronchitis viral. | 12 | 2 Only Grade 3 adverse reactions occurred. |
| General disorders and administration site conditions | ||
| Fatigue Fatigue includes asthenia, and fatigue. | 39 | 2 |
| Pyrexia | 21 | 2 |
| Edema peripheral Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling. | 20 | 0 |
| Psychiatric disorders | ||
| Insomnia | 33 | 6 |
| Vascular disorders | ||
| Hypertension Hypertension includes blood pressure increased, and hypertension. | 32 | 21 |
| Gastrointestinal disorders | ||
| Diarrhea | 29 | 0 |
| Nausea | 21 | 0 |
| Vomiting | 15 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough Cough includes cough, and productive cough. | 24 | 0 |
| Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. | 23 | 2 |
| Nervous system disorders | ||
| Headache | 23 | 0 |
| Peripheral sensory neuropathy | 11 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 17 | 2 |
| Musculoskeletal chest pain | 11 | 0 |
| Laboratory Abnormality | DARZALEX FASPRO-Kd Denominator is based on the safety population treated with DARZALEX FASPRO-Kd (N=66). | |
|---|---|---|
| All Grades (%) | Grades 3–4 (%) | |
| Decreased platelets | 88 | 18 |
| Decreased lymphocytes | 83 | 50 |
| Decreased leukocytes | 68 | 18 |
| Decreased neutrophils | 55 | 15 |
| Decreased hemoglobin | 47 | 6 |
| Decreased corrected calcium | 45 | 2 |
| Increased alanine aminotransferase (ALT) | 35 | 5 |
| Adverse Reaction | DARZALEX FASPRO (N=260) | Intravenous Daratumumab (N=258) | ||
|---|---|---|---|---|
| All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | |
| Infections | ||||
| Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection. | 24 | 1 Only Grade 3 adverse reactions occurred. | 22 | 1 |
| Pneumonia Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. | 8 | 5 | 10 | 6 Grade 5 adverse reactions occurred. |
| Gastrointestinal disorders | ||||
| Diarrhea | 15 | 1 | 11 | 0.4 |
| Nausea | 8 | 0.4 | 11 | 0.4 |
| General disorders and administration site conditions | ||||
| Fatigue Fatigue includes asthenia, and fatigue. | 15 | 1 | 16 | 2 |
| Infusion reactions Infusion reactions includes terms determined by investigators to be related to infusion. | 13 | 2 | 34 | 5 |
| Pyrexia | 13 | 0 | 13 | 1 |
| Chills | 6 | 0.4 | 12 | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 10 | 2 | 12 | 3 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough Cough includes cough, and productive cough. | 9 | 1 | 14 | 0 |
| Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. | 6 | 1 | 11 | 1 |
| Laboratory Abnormality | DARZALEX FASPRO Denominator is based on the safety population treated with DARZALEX FASPRO (N=260) and Intravenous Daratumumab (N=258). | Intravenous Daratumumab | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Decreased leukocytes | 65 | 19 | 57 | 14 |
| Decreased lymphocytes | 59 | 36 | 56 | 36 |
| Decreased neutrophils | 55 | 19 | 43 | 11 |
| Decreased platelets | 43 | 16 | 45 | 14 |
| Decreased hemoglobin | 42 | 14 | 39 | 16 |
| DARZALEX FASPRO (N=193) | ACTM (N=196) | |||
|---|---|---|---|---|
| Adverse Reaction | All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
| Key: ACTM=active monitoring | ||||
| Infections | ||||
| Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, adenoviral upper respiratory infection, catarrh, influenza, influenza like illness, laryngitis, metapneumovirus infection, nasal congestion, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract congestion, respiratory tract infection, respiratory tract infection viral, sinus congestion, sinusitis, throat irritation, tonsillitis, tracheitis, upper respiratory tract congestion, upper respiratory tract infection, upper respiratory tract infection bacterial, upper-airway cough syndrome, and viral upper respiratory tract infection. | 66 | 1 Only Grade 3 adverse reactions occurred. | 27 | 0 |
| Pneumonia Pneumonia includes covid-19 pneumonia, lower respiratory tract infection, organizing pneumonia, pneumonia, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, and pneumonia viral. | 16 | 7 Fatal adverse reactions occurred for Pneumonia: n=1 (1%) in the DARZALEX FASPRO arm. | 8 | 3 |
| Rhinitis Rhinitis includes rhinitis, rhinitis atrophic, rhinorrhea, rhinovirus infection, and viral rhinitis. | 10 | 0 | 2 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain Musculoskeletal pain includes arthralgia, axillary pain, back pain, breast pain, chest pain, facial spasm, fibromyalgia, flank pain, groin pain, muscle fatigue, muscle rupture, muscle spasms, muscle strain, muscle tightness, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, pain in jaw, periarthritis, radicular pain, rotator cuff syndrome, spinal pain, spinal stenosis, and tendon pain. | 59 | 1 | 42 | 3 |
| General disorders and administration site conditions | ||||
| Fatigue Fatigue includes asthenia, fatigue, and malaise. | 42 | 3 | 21 | 1 |
| Injection site reactions Injection site reaction includes injection site discoloration, injection site erythema, injection site hemorrhage, injection site induration, injection site edema, injection site pain, injection site pruritus, injection site rash, injection site swelling, injection site urticaria, injection site vesicles, and injection site warmth. | 20 | 0 | 0 | 0 |
| Infusion-related reactions Infusion-related reactions includes terms determined by investigators to be related to infusion. | 17 | 1 | 0 | 0 |
| Pyrexia | 17 | 0 | 3 | 1 |
| Edema Edema includes brain edema, eye swelling, eyelid edema, generalized edema, joint swelling, laryngeal edema, localized edema, edema, edema peripheral, peripheral swelling, post procedural edema, post procedural swelling, swelling face, and swelling of eyelid. | 15 | 1 | 5 | 1 |
| Gastrointestinal disorders | ||||
| Diarrhea | 27 | 2 | 5 | 1 |
| Nausea | 19 | 0 | 5 | 0 |
| Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain. | 17 | 1 | 7 | 2 |
| Skin and subcutaneous tissue disorders | ||||
| Rash Rash includes acne, dermatitis, dermatitis allergic, dermatitis bullous, dermatitis contact, drug eruption, drug hypersensitivity, eczema, eczema asteatotic, eczema infected, erysipelas, erythema, erythema multiforme, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, seborrheic dermatitis, seborrheic keratosis, skin lesion, skin reaction, skin ulcer, and urticaria. | 27 | 1 | 6 | 1 |
| Psychiatric disorders | ||||
| Sleep disorder Sleep disorder includes insomnia, restless legs syndrome, sleep apnea syndrome, sleep deficit, and sleep disorder. | 24 | 1 | 5 | 0 |
| Nervous system disorders | ||||
| Sensory neuropathy Sensory neuropathy includes allodynia, anosmia, burning sensation, carpal tunnel syndrome, cervical radiculopathy, cervicobrachial syndrome, dysesthesia, hypoesthesia, hypoesthesia oral, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, pharyngeal paresthesia, polyneuropathy, and sensory disturbance. | 20 | 0 | 8 | 0 |
| Headache Headache includes headache, migraine, and vascular headache. | 18 | 1 | 8 | 0 |
| Dizziness Dizziness includes dizziness, and dizziness postural. | 12 | 0 | 5 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough Cough includes cough, and productive cough. | 19 | 0 | 7 | 0 |
| Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. | 18 | 1 | 6 | 1 |
| DARZALEX FASPRO Denominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=191 for DARZALEX FASPRO and N=191 for ACTM. | ACTM | |||
|---|---|---|---|---|
| Laboratory Abnormality | All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) |
| Key: ACTM=active monitoring | ||||
| Hematology | ||||
| Decreased lymphocytes | 47 | 6 | 12 | 3 |
| Decreased hemoglobin | 42 | 0 | 44 | 2 |
| Decreased leukocytes | 34 | 3 | 27 | 2 |
| Decreased neutrophils | 34 | 6 | 29 | 4 |
| Decreased platelets | 19 | 1 | 9 | 1 |
| Chemistry | ||||
| Decreased albumin | 28 | 0 | 15 | 1 |
| Increased alanine aminotransferase (ALT) | 25 | 1 | 13 | 1 |
| Decreased sodium | 24 | 3 | 19 | 2 |
| Increased creatinine | 20 | 0 | 13 | 1 |
| Increased aspartate aminotransferase (AST) | 20 | 0 | 12 | 1 |
| Adverse Reaction | DARZALEX FASPRO-VCd (N=193) | VCd (N=188) | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Infections | ||||
| Upper respiratory tract infection Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. | 40 | 1 Only Grade 3 adverse reactions occurred. | 21 | 1 |
| Pneumonia Pneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. | 15 | 10 | 9 | 5 |
| Gastrointestinal disorders | ||||
| Diarrhea | 36 | 6 | 30 | 4 |
| Constipation | 34 | 2 | 29 | 0 |
| Nervous system disorders | ||||
| Peripheral sensory neuropathy | 31 | 3 | 20 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. | 26 | 4 | 20 | 4 |
| Cough Cough includes cough, and productive cough. | 20 | 1 | 11 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 12 | 2 | 6 | 0 |
| Arthralgia | 10 | 0 | 5 | 0 |
| Muscle spasms | 10 | 1 | 5 | 0 |
| Cardiac disorders | ||||
| Arrhythmia Arrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia | 11 | 4 | 5 | 2 |
| General disorders and administration site conditions | ||||
| Injection site reactions Injection site reactions includes terms determined by investigators to be related to daratumumab injection. | 11 | 0 | 0 | 0 |
| Laboratory Abnormality | DARZALEX FASPRO-VCd | VCd | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Denominator is based on the number of patients with a baseline and post-baseline laboratory value for each laboratory test, N=188 for DARZALEX FASPRO-VCd and N=186 for VCd. | ||||
| Decreased lymphocytes | 81 | 54 | 71 | 46 |
| Decreased hemoglobin | 66 | 6 | 70 | 6 |
| Decreased leukocytes | 60 | 7 | 46 | 4 |
| Decreased platelets | 46 | 3 | 40 | 4 |
| Decreased neutrophils | 30 | 6 | 18 | 4 |
Warnings & Cautions for Darzalex Faspro
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. 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). 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. 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. 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. 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.
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. 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.
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.
Neutropenia Daratumumab may increase neutropenia induced by background therapy. 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.
Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy. Consider withholding DARZALEX FASPRO until recovery of platelets.
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. 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 during pregnancy.
Interference with Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum.
The determination of a patient's ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO.
Interference with Determination of Complete Response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.
Drug Interactions with Darzalex Faspro
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 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.
Pregnancy Safety for Darzalex Faspro
Pregnancy Risk Summary DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data ). There are no available data on the use of DARZALEX FASPRO in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
Animal reproduction studies have not been conducted. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. The combination of DARZALEX FASPRO and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child.
Lenalidomide, thalidomide and pomalidomide are only available through a REMS program. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy. Clinical Considerations Fetal/Neonatal Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta.
Based on its mechanism of action, DARZALEX FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed. Data Animal Data DARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase.
Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs). No systemic exposure of hyaluronidase was detected in monkeys given 220,000 U/kg subcutaneously (440 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 360,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 720 times higher than the human dose.
There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 1,100,000 U/kg hyaluronidase subcutaneously, which is 2,200 times higher than the human doses.
Pediatric Use of Darzalex Faspro
Pediatric Use Safety and effectiveness of DARZALEX FASPRO in pediatric patients have not been established.
Contraindications for Darzalex Faspro
DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.
Clinical Studies of Darzalex Faspro
Newly Diagnosed Multiple Myeloma In Combination with Bortezomib, Lenalidomide and Dexamethasone in Patients Eligible for Autologous Stem Cell Transplant The efficacy of DARZALEX FASPRO with bortezomib, lenalidomide and dexamethasone (DARZALEX FASPRO-VRd) during induction and consolidation was evaluated in PERSEUS (NCT03710603), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma eligible for ASCT. Enrollment was limited to patients 70 years of age and younger. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT.
Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m 2 body surface area twice weekly for two weeks days of each 28-day cycle for weeks 1–16 during induction and weeks 1–8 during consolidation. On the days of DARZALEX FASPRO injection, the dexamethasone dose was administered orally or intravenously as a pre-injection medication. Following consolidation, patients received an investigational treatment regimen for maintenance that included DARZALEX FASPRO in combination with lenalidomide or lenalidomide alone.
The trial was not designed to isolate the effect of DARZALEX FASPRO in the maintenance phase of treatment. The efficacy of DARZALEX FASPRO in combination with lenalidomide for maintenance has not been established. The major efficacy outcome measure was progression-free survival (PFS) by independent review committee (IRC) based on IMWG response criteria.
A total of 709 patients were randomized: 355 to the DARZALEX FASPRO-VRd arm and 354 to the VRd arm. Fifty-one percent had ISS Stage I, 34% had ISS Stage II, 15% had ISS Stage III disease. High-risk cytogenetics (presence of del(17p), t(4;14), t) were present in 22% of patients.
PERSEUS demonstrated an improvement in PFS in the DARZALEX FASPRO-VRd arm as compared to the VRd arm; the median PFS had not been reached in either arm. Treatment with DARZALEX FASPRO-VRd resulted in a reduction in the risk of disease progression or death by 60% compared to VRd alone (HR: 0.40; p-value < 0.0001). Figure 1: Kaplan-Meier Curve of PFS in PERSEUS Additional efficacy results from PERSEUS are presented in Table 28.
Table 28: Efficacy Results through End of Consolidation from PERSEUS In Combination with Bortezomib, Lenalidomide and Dexamethasone in Patients Who Are Ineligible for ASCT The efficacy of DARZALEX FASPRO with bortezomib, lenalidomide and dexamethasone (DARZALEX FASPRO-VRd) versus bortezomib, lenalidomide and dexamethasone (VRd) was evaluated in CEPHEUS (NCT03652064), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or refused ASCT as initial therapy. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg/m 2 body surface area twice weekly days in repeated 21-day (3-week) cycles from Cycles 1–8. The effectiveness of DARZALEX FASPRO-VRd has not been established in patients who refused ASCT as initial therapy.
A total of 395 patients were randomized: 197 to the DARZALEX FASPRO-VRd arm and 198 to the VRd arm. Thirty-four percent had ISS Stage I, 38% had ISS Stage II, and 28% had ISS Stage III disease. The trial demonstrated a statistically significant improvement in overall MRD negativity rate, PFS, CR or better rate, and sustained MRD negativity rate, as shown in Table 29 and Figure 2.
Table 29: Efficacy Outcomes from CEPHEUS Based on intent-to-treat population unless otherwise noted., The hierarchical testing order in the CEPHEUS study was overall MRD negativity rate followed by CR or better rate, PFS, and sustained MRD negativity rate. In Combination with Bortezomib, Melphalan and Prednisone in Patients Ineligible for Autologous Stem Cell Transplant The efficacy of DARZALEX FASPRO with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. Eligible patients were required to have newly diagnosed multiple myeloma who are ineligible for transplant.
The major efficacy outcome measure was overall response rate (ORR). A total of 67 patients received DARZALEX FASPRO with VMP. Efficacy results are summarized in Table 30.
The median duration of follow-up for patients was 6.9 months. Table 30: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-VMP Figure 1 Figure 2
Relapsed/Refractory Multiple Myeloma In Combination with Lenalidomide and Dexamethasone The efficacy of DARZALEX FASPRO with lenalidomide and dexamethasone (DARZALEX FASPRO-Rd) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. The major efficacy outcome measure was ORR. A total of 65 patients received DARZALEX FASPRO with Rd.
Patients had received a median of 1 prior line of therapy. Efficacy results are summarized in Table 31. The median duration of follow-up for patients was 7.1 months.
Table 31: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-Rd In Combination with Pomalidomide and Dexamethasone The efficacy of DARZALEX FASPRO with pomalidomide and dexamethasone (DARZALEX FASPRO-Pd) versus pomalidomide and dexamethasone (Pd) alone was evaluated in APOLLO (NCT03180736), an open-label, randomized, active-controlled trial. A total of 304 patients were randomized: 151 to the DARZALEX FASPRO-Pd arm and 153 to the Pd arm. All patients received a prior treatment with a PI and lenalidomide, and 56% of patients received prior ASCT.
The majority of patients were refractory to lenalidomide (80%), a PI (48%), or both an immunomodulatory agent and a PI (42%). APOLLO demonstrated an improvement in PFS in the DARZALEX FASPRO-Pd treatment group as compared to the Pd treatment group; the median PFS was 12.4 months in the DARZALEX FASPRO-Pd treatment group and 6.9 months in the Pd treatment group (HR: 0.63; p-value = 0.0018), representing a 37% reduction in the risk of disease progression or death for patients treated with DARZALEX FASPRO-Pd versus Pd. Figure 3: Kaplan-Meier Curve of PFS in APOLLO Additional efficacy results from APOLLO are presented in Table 32.
Median OS was not reached for either treatment group. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within 6 months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). A total of 66 patients received DARZALEX FASPRO with Kd.
A total of 79% of patients had a prior ASCT; 91% of patients received a prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide. Efficacy results are summarized in Table 33.
At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated maintained response for at least 6 months and maintained response for at least 9 months. Table 33: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO-Kd Monotherapy The efficacy of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA (NCT03277105), an open-label, randomized, non-inferiority study. Eligible patients were required to have relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent.
The major efficacy outcome measures were ORR by the IMWG response criteria and maximum C trough at pre-dose Cycle 3 Day 1. Randomization was stratified by body weight, myeloma type, and number of prior lines of therapy. A total of 522 patients were randomized: 263 to the DARZALEX FASPRO arm and 259 to the intravenous daratumumab arm.
The median weight was 73 kg (range: 29 to 138). Patients had received a median of 4 prior lines of therapy. A total of 51% of patients had a prior ASCT; 100% of patients received both a PI and an immunomodulatory agent.
Forty-nine percent of patients were refractory both a PI and an immunomodulatory agent. Eighty-two percent of patients were refractory to their last line of prior systemic therapy. The results show that DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously is non-inferior to daratumumab 16 mg/kg administered intravenously in terms of ORR and maximum trough concentration.
Median progression-free survival was 5.6 months in the DARZALEX FASPRO arm and 6.1 months in the intravenous daratumumab arm. ORR results are provided in Table 34. Table 34: Efficacy Results from COLUMBA Figure 3
High-Risk Smoldering Multiple Myeloma Monotherapy
The efficacy of DARZALEX FASPRO as monotherapy versus active monitoring was evaluated in AQUILA (NCT03301220), an open-label, randomized trial in patients with high-risk smoldering multiple myeloma. A total of 390 patients were randomized: 194 to the DARZALEX FASPRO arm and 196 to the active monitoring arm. Forty-one percent of patients had 2 or more of the following criteria for high-risk smoldering multiple myeloma: serum monoclonal protein level >2 g/dL, involved-to-uninvolved serum-free light chain ratio >20, and bone marrow plasma cells >20%.
DARZALEX FASPRO is only indicated for patients with high-risk smoldering multiple myeloma. It is not indicated for other risk categories. PFS results are shown in Figure 4.
Figure 4: Kaplan-Meier Curve of PFS in AQUILA Additional efficacy results from AQUILA are presented in Table 35. Table 35: Efficacy Results from AQUILA Based on intent-to-treat population per investigator assessment Figure 4
Light Chain Amyloidosis In Combination with Bortezomib, Cyclophosphamide and Dexamethasone The efficacy of DARZALEX FASPRO with VCd was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial. Eligible patients were required to have newly diagnosed light chain (AL) amyloidosis with at least one affected organ, measurable hematologic disease, Cardiac Stage I–IIIA (based on European Modification of Mayo 2004 Cardiac Stage), and NYHA Class I–IIIA. Patients with NYHA Class IIIB and IV were excluded.
When DARZALEX FASPRO and dexamethasone were administered on the same day, dexamethasone 20 mg was administered before DARZALEX FASPRO with the remaining dose of dexamethasone administered after DARZALEX FASPRO if applicable. The major efficacy outcome measure was confirmed hematologic complete response (HemCR) rate based on Consensus Criteria as determined by the Independent Review Committee (negative serum and urine immunofixation, involved free light chain level decrease to less than the upper limit of normal, and normal free light chain ratio). Randomization was stratified by Cardiac Stage (European Modification of Mayo 2004 Cardiac Stage) countries that typically offer autologous stem cell transplant (ASCT) for patients with light chain (AL) amyloidosis, and renal function.
A total of 388 patients were randomized: 195 to DARZALEX FASPRO-VCd and 193 to VCd. Vital organ involvement was: cardiac 71%, renal 59% and hepatic 8%. The majority (79%) of patients had lambda free light chain disease.
Efficacy results are summarized in Table 36. The median duration of HemCR had not been reached in either arm. After a median follow-up of 61.4 months, ANDROMEDA demonstrated an improvement in major organ deterioration progression free survival (MOD-PFS) in the DARZALEX FASPRO-VCd arm as compared to the VCd arm (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001), representing a 53% reduction in the risk of hematologic progression, major organ deterioration, or death in patients treated in the DARZALEX FASPRO-VCd arm.
The median MOD-PFS was not reached in the DARZALEX FASPRO-VCd arm and was 30.2 months in the VCd arm. Figure 5: Kaplan-Meier Curve of MOD-PFS in ANDROMEDA After a median follow-up of 61.4 months, ANDROMEDA demonstrated an improvement in overall survival (OS) in the DARZALEX FASPRO-VCd arm as compared to the VCd arm (HR=0.62; 95% CI: 0.42, 0.90; p=0.0121), representing a 38% reduction in the risk of death in patients treated in the DARZALEX FASPRO-VCd arm.
| DARZALEX FASPRO-VRd (n=355) | VRd (n=354) | |
|---|---|---|
| VRd = bortezomib-lenalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval | ||
| Overall response (sCR+CR+VGPR+PR), n (%) Based on intent-to-treat population | 338 (95.2%) | 326 (92.1%) |
| Stringent complete response (sCR) | 67 (18.9%) | 46 (13.0%) |
| Complete response (CR) | 91 (25.6%) | 77 (21.8%) |
| Very good partial response (VGPR) | 165 (46.5%) | 168 (47.5%) |
| Partial response (PR) | 15 (4.2%) | 35 (9.9%) |
| CR or better (sCR+CR), n (%) | 158 (44.5%) | 123 (34.7%) |
| 95% CI (%) Exact 95% confidence interval | (39.3%, 49.9%) | (29.8%, 40.0%) |
| MRD negativity rate, Based on threshold of 10 -5 using a next-generation sequencing assay (clonoSEQ), Patients achieved both MRD negativity (threshold of 10 -5 ) and response of CR or better, n (%) | 204 (57.5%) | 115 (32.5%) |
| 95% CI (%) | (52.1%, 62.7%) | (27.6%, 37.6%) |
| MRD negativity rate in patients with CR or better, Based on patients with CR or better response by the end of consolidation | ||
| Number of patients with CR or better | n=158 | n=123 |
| MRD negativity rate n (%) | 121 (76.6%) | 72 (58.5%) |
| 95% CI (%) | (69.2%, 82.9%) | (49.3%, 67.3%) |
| DARZALEX FASPRO-VRd (N=197) | VRd (N=198) | |
|---|---|---|
| VRd=bortezomib-lenalidomide-dexamethasone; PFS=progression-free survival; MRD=minimal residual disease; CI=confidence interval; NR = not reached; NE = not evaluable. | ||
| PFS based on IRC Interim analysis: Median follow-up of 39 months (cut-off date 08 September 2022). | ||
| Number of events, n (%) | 46 (23.4%) | 68 (34.3%) |
| Median, months with 95% CI | NR (NE, NE) | NR (NE, NE) |
| Hazard ratio with 95% CI Hazard ratio and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, III), and age/transplant eligibility (<70 years ineligible, or <70 years and refusal to transplant, or ≥70 years) as randomized. A hazard ratio <1 indicates an advantage for D-VRd. | 0.60 (0.41, 0.88) | |
| p-value p-value is based on the log-rank test stratified with ISS staging (I, II, III), and age/transplant eligibility (<70 years ineligible, or <70 years and refusal to transplant, or ≥70 years) as randomized. | 0.0078 | |
| MRD negativity rate n (%) Primary analysis: Median follow-up of 22 months (cut-off date 08 April 2021)., Patients achieved both MRD negativity (threshold of 10 -5 ) and CR or better. All MRD testing was performed with a next-generation sequencing assay (clonoSEQ). | 103 (52.3%) | 69 (34.8%) |
| p-value p-value from Cochran Mantel-Haenszel Chi-Squared test. | 0.0005 | |
| Overall CR or better (sCR+CR) n (%) | 150 (76.1%) | 116 (58.6%) |
| p-value | 0.0002 | |
| MRD negativity rate in patients with CR or better, Patients achieving MRD negativity (threshold of 10 -5 ) among only patients achieving a response of CR or better. | ||
| Number of patients with CR or better | n=150 | n=116 |
| MRD negativity rate n (%) | 103 (68.7%) | 69 (59.5%) |
| 95% CI (%) Exact 95% confidence interval. | (60.6%, 76.0%) | (50.0%, 68.5%) |
| Sustained MRD negativity rate n (%), Sustained MRD negativity is defined as confirmed MRD negative status at two examinations at least 1 year apart without MRD positive status in between. | 84 (42.6%) | 50 (25.3%) |
| p-value p-value from Fisher's exact test. | 0.0003 | |
| Overall response (sCR+CR+VGPR+PR) n(%) Final analysis: Median follow-up of 59 months (cut-off date 07 May 2024). | 191 (97.0%) | 185 (93.4%) |
| Stringent Complete Response (sCR) | 128 (65.0%) | 89 (44.9%) |
| Complete response (CR) | 32 (16.2%) | 33 (16.7%) |
| Very good partial response (VGPR) | 23 (11.7%) | 49 (24.7%) |
| Partial response (PR) | 8 (4.1%) | 14 (7.1%) |
| DARZALEX FASPRO-VMP (N=67) | |
|---|---|
| CI=confidence interval | |
| Overall response rate (sCR+CR+VGPR+PR), n (%) Based on treated patients | 59 (88%) |
| 95% CI (%) | (78%, 95%) |
| Stringent complete response (sCR) | 5 (8%) |
| Complete response (CR) | 7 (10%) |
| Very good partial response (VGPR) | 31 (46%) |
| Partial response (PR) | 16 (24%) |
| DARZALEX FASPRO-Rd (N=65) | |
|---|---|
| CI=confidence interval | |
| Overall response rate (sCR+CR+VGPR+PR), n (%) Based on treated patients | 59 (91%) |
| 95% CI (%) | (81%, 97%) |
| Stringent complete response (sCR) | 4 (6%) |
| Complete response (CR) | 8 (12%) |
| Very good partial response (VGPR) | 30 (46%) |
| Partial response (PR) | 17 (26%) |
| DARZALEX FASPRO-Pd (n=151) | Pd (n=153) | |
|---|---|---|
| Pd=pomalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval | ||
| Overall response (sCR+CR+VGPR+PR) n (%) | 104 (68.9%) | 71 (46.4%) |
| P-value p-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors | <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 rate Based on the intent-to-treat population, Based on threshold of 10 -5 using a next-generation sequencing assay (clonoSEQ). n (%) | 13 (8.6%) | 3 (2.0%) |
| 95% CI (%) | (4.7%, 14.3%) | (0.4%, 5.6%) |
| P-value p-value from Fisher's exact test. | 0.0102 | |
| MRD negativity rate in patients with CR or better | ||
| Number of patients with CR or better | N=37 | N=6 |
| MRD negativity rate n (%) | 13 (35.1%) | 3 (50.0%) |
| 95% CI (%) | (20.2%, 52.5%) | (11.8%, 88.2%) |
| DARZALEX FASPRO-Kd (N=66) | |
|---|---|
| CI=confidence interval | |
| Overall response rate (sCR+CR+VGPR+PR), n (%) Based on treated patients | 56 (84.8%) |
| 95% CI (%) | (73.9%, 92.5%) |
| Stringent complete response (sCR) | 11 (16.7%) |
| Complete response (CR) | 14 (21.2%) |
| Very good partial response (VGPR) | 26 (39.4%) |
| Partial response (PR) | 5 (7.6%) |
| DARZALEX FASPRO (N=263) | Intravenous Daratumumab (N=259) | |
|---|---|---|
| Overall response (sCR+CR+VGPR+PR), n (%) Based on intent-to-treat population. | 108 (41%) | 96 (37%) |
| 95% CI (%) | (35%, 47%) | (31%, 43%) |
| Ratio of response rates (95% CI) | 1.11 (0.89, 1.37) | |
| CR or better, n (%) | 5 (1.9%) | 7 (2.7%) |
| Very good partial response (VGPR) | 45 (17%) | 37 (14%) |
| Partial response (PR) | 58 (22%) | 52 (20%) |
| DARZALEX FASPRO (n=194) | Active Monitoring (n=196) | |
|---|---|---|
| Overall response (sCR+CR+VGPR+PR), n (%) | 123 (63.4%) | 2 (1.0%) |
| Stringent complete response (sCR) | 7 (3.6%) | 0 |
| Complete response (CR) | 10 (5.2%) | 0 |
| Very good partial response (VGPR) | 41 (21.1%) | 1 (0.5%) |
| Partial response (PR) | 65 (33.5%) | 1 (0.5%) |
| DARZALEX FASPRO-VCd (n=195) | VCd (n=193) | |
|---|---|---|
| VCd=bortezomib-cyclophosphamide-dexamethasone | ||
| Hematologic complete response (HemCR), n (%) | 82 (42%) | 26 (13%) |
| p-value p-value from Cochran Mantel-Haenszel Chi-Squared test. | <0.0001 | |
| Very good partial response (VGPR), n (%) | 71 (36%) | 69 (36%) |
| Partial response (PR), n (%) | 26 (13%) | 53 (27%) |
| Hematologic VGPR or better (HemCR + VGPR), n (%) | 153 (78%) | 95 (49%) |
| Major organ deterioration progression-free survival Major organ deterioration-PFS defined as hematologic progression, major organ (cardiac or renal) deterioration or death, Hazard ratio with 95% CI | 0.58 (0.37, 0.92) | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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