Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Daratumumab · 30 trials · 13 indications
The time from iFIT1 randomisation to progression or death from any cause. Participants alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free.
The time from iFIT2 randomisation to the first of the following events: grade 4 haematological AEs, grade 3 and 4 non-haematological AEs (including SPMs), discontinuation of trial treatment, progression or death. Participants event-free at the time of analysis will be censored at their last date known to be alive and event-free.
PFS: The time from iFIT3 randomisation to progression or death from any cause. Participants alive and progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. QoL: The GHS/QoL scale score of the EORTC QLQ-C30 questionnaire. The QoL primary endpoint is measured at 30 months (2.5 years) after iFIT3 randomisation.
Number of participants with SAEs will be reported. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect, and suspects transmission of any infectious agent via a medicinal product.
Number of participants with AESI, that is, reactivation of HBV infection, will be reported.
Number of participants with pregnancies or partner pregnancies will be reported using the appropriate pregnancy notification form.
Number of Participants with Abnormal Pregnancies as SAE will be reported.
PFS is defined as the time from the date of randomization to the date of first documented disease progression, as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first.
Percentage of participants who achieved MRD negative (MRD conversion) status from baseline to 12 months after maintenance treatment was defined as percentage of participants who were MRD positive at baseline (randomization) and achieved MRD negative status (at 10\^-5) during the time period from randomization to 12 months plus 2 months window, but prior to progressive disease (PD) and subsequent anti-myeloma therapy.
Overall MRD negativity rate was defined as the percentage of participants who achieved complete response (CR) or better response and had MRD negative status (at 10\^5) by bone marrow biopsy or aspirate after randomization but prior to progressive disease (PD), subsequent anti-myeloma therapy, or both. CR or better rate was defined as the percentage of participants achieving CR or stringent complete response (sCR) prior to subsequent anti-myeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (\<) 5 percent (%) plasma cells (PCs) in bone marrow. sCR was defined as CR plus normal free light chain (FLC) ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Overall MRD negativity rate was defined as the percentage of participants who achieved CR or better response and had MRD negative status (at 10\^5) by bone marrow biopsy or aspirate after randomization but prior to PD, subsequent anti-myeloma therapy, or both. CR or better rate was defined as the percentage of participants achieving CR or sCR prior to subsequent anti-myeloma therapy in accordance with the IMWG criteria during or after the study treatment. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and \< 5 % PCs in bone marrow. sCR was defined as CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
PFS is duration from date of randomization to either PD (as per international myeloma working group \[IMWG\] criteria) or death whichever occurs first. PD: Increase of 25 percent (%) from lowest response value in one of following: Serum M-component and urine M-component (absolute increase must be greater than or equal to \[\>=\]0.5 gram per deciliter \[g/dL\] and \>=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be \>10 mg/dL); only in participants without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow plasma cell (PC) percentage (absolute percentage must be \>=10%); definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium \>11.5 mg/dL).
Overall CHR rate was defined as percentage of participants who achieved CHR, according to the International Amyloidosis Consensus Criteria. CHR: normalization of free light chain levels and ratio, negative serum, and urine immunofixation. If involved free light chain (iFLC) is less than (\<) upper limit of normal (ULN) and serum and urine Immunofixation electrophoresis (IFE) are negative, then neither a normal uninvolved free light chain (uFLC) level nor a normal free light chain (FLC) ratio are required for complete response (CR).
Response assessment will be done at each restaging. The best overall response will be defined as the best response between the date of beginning of therapy and the last response evaluation. Patients without response assessment (due to whatever reason) will be considered as non-responders.
Number of participants with cardiac events of any toxicity grade will be reported.
Ctrough is defined as the observed concentration immediately prior to the next study treatment administration.
MRD negative disease (MRD-) is defined as zero residual sequence cells detected at a level of one million cells. At time of final analysis, the 2-year MRD- rate will be summarized as a proportion with a 90% exact binomial confidence interval
Complete response based on the modified National Comprehensive Cancer Network (NCCN) criteria was defined as: less than 5 percent (%) blasts in the bone marrow; no evidence of circulating blasts or extramedullary disease; full recovery of peripheral blood counts: platelets greater than (\>)100\*10\^9 cells/liter (L) and absolute neutrophil count (ANC) \>1.0\*10\^9 cells/L. This outcome measure was planned to be analyzed for specified arm only.
Complete response based on the modified NCCN criteria was defined as: less than 5% blasts in the bone marrow; no evidence of circulating blasts or extramedullary disease; full recovery of peripheral blood counts: platelets \>100\*10\^9 cells/L and ANC \>1.0\*10\^9 cells/L. This outcome measure was planned to be analyzed for specified arms only.
ORR was defined as the percentage of participants who achieved partial response (PR) or better according to international myeloma working group (IMWG) criteria. IMWG criteria for PR: greater than or equal to (\>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to less than (\<) 200 milligrams (mg) per 24 hours, If the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%. In addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required.
VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response \[sCR\]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are adverse events (AEs) which will occur up to 2 years that were absent before treatment or that worsened relative to pre-treatment state.
Dose limiting toxicity defined as an adverse event or adverse drug reaction experienced by the participants during observation of 28 days (Part 1) of treatment Cycle 1.
Overall response was defined as the percentage of participants who achieved complete response (CR) or partial response (PR) per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin lymphoma: LUGANO classification based on blinded independent central review (BICR). As per Revised Response Criteria for Malignant Lymphoma, Lymph node measurements were taken from Computed Tomography (CT), CT portion of the Positron Emission Tomography/Computed Tomography (PET/CT), where applicable. CR: complete disappearance of all evidence of disease; PR as a greater than (\>) 50 percent (%) decrease in the sum of the products of the maximal perpendicular diameters of measured lesions (SPD) and no new sites.
Percentage of participants who achieved CR or VGPR (as per International Myeloma Working Group \[IMWG\] criteria) was reported. CR: negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than (\<) 5 percent (%) plasma cells (PC) in bone marrow. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to (\>=) 90% reduction in serum M-protein plus urine M-protein level \< 100 milligram per 24 hours (mg/24hours).
Percentage of participants who had achieved sCR as determined by the validated computer algorithm according to the International Myeloma Working Group (IMWG) criteria, by the end of post-autologous stem cell transplantation (post-ASCT) consolidation treatment were reported. Complete response (CR) is defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (\<) 5 percent (%) PCs in bone marrow. sCR is defined as in addition to CR a normal FLC ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry.
Percentage of participants who achieved a CR by IMWG Criteria were reported. CR was defined as CR plus stringent complete Response (sCR) by IMWG criteria. Per IMWG criteria, CR response was defined as a negative immunofixation on the serum and urine, and less than (\<) 5 percentage (%) plasma cells in bone marrow; sCR was defined as CR plus normal free light chain (FLC) ratio, and absence of clonal plasma cells by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Progressive disease (PD) or death rate were reported. PD or death rate per patient-year was defined as number of events (PD or death) divided by total progression-free survival (PFS) for all participants.
Tolerance criteria according to NCI-CTCAE v5 criteria is defined as occurence of infusion related reactions; Cytokine release syndrome is characterized by increased levels of serum pro-inflammatory mediators; Main hemostasis parameters (prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), thromobin time (TT), and D-dimer (DD); Variation in main biological parameters (blood ionogram).
The cessation of disease progression at day 6 (D6) will be assessed by evaluating the change in the percentage of body surface area with skin detachment (detached and/or bullous surfaces, and/or associated with Nikolsky's sign) between the baseline (before daratumumab administration) and day 6 (D6), according to the following rules : * ≤ 2% for Stevens-Johnson Syndrome, * ≤ 5% for overlap syndrome * ≤ 10% for Lyell syndrome And without any new lesion with skin detachment. The percentage of body surface area with skin detachment will be evaluated based on the stable burn table using the E-Burn® application Day 6 after an intravenous injection of darzalex (16mg/kg) in addition to the reference symptomatic treatment (Day 1 = infusion of darzalex treatment)
Occurrence of grade \>=3 cardiovascular, renal, thyroid or intestinal adverse events, according to NCI-CTCAE v5 criteria.
To characterize the safety and tolerability of subcutaneous daratumumab administered in the thigh vs the abdomen in patients with plasma cell disorders. Frequency and incidence rate of adverse events by type, severity, timing, and attribution to study drug, according to the NCI-CTCAE version 5.0.
The dose limiting toxicities are based on drug related adverse events and defined as any of the following events: hematological or non-hematological toxicity of grade 3 or higher.
The dose limiting toxicities are based on drug related adverse events and defined as any of the following events: hematological or non-hematological toxicity of grade 3 or higher.
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect, and suspects transmission of any infectious agent via a medicinal product.
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect, and suspects transmission of any infectious agent via a medicinal product.
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Cmax is the maximum observed serum concentration.
Ctrough is the observed concentration of daratumumab prior to the next drug administration.
The safety and tolerability of daratumumab following a single subcutaneous (SC) administration in healthy participants will be assessed.
The safety and tolerability of daratumumab following a single subcutaneous (SC) administration in healthy participants will be assessed.
The Cmax is the maximum observed plasma concentration.
The (Ctrough) is the concentration before dosing just prior to the beginning of a doing interval.
AUC is defined as area under the plasma concentration-time curve.
Systemic Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC \[0-infinity\]).
Elimination half-life (t\[1/2\]) is associated with the terminal slope (lambda \[z\]) of the semi-logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).
The Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
Number of Participants With Dose Limiting Toxicity During Cycle 1.
The Dose-Limiting Toxicities (DLTs) are based on drug-related adverse events and defined as any of the following events: Infusion-related reactions, non-hematologic toxicity of Grade 3 or higher, or hematologic toxicity.
An AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
| Arm | Type | Description |
|---|---|---|
| DRd induction | ACTIVE_COMPARATOR | All participants will receive standard of care treatment with daratumumab, lenalidomide, and dexamethasone for an initial 6 cycles. |
| iFIT1 - DRd to PD | ACTIVE_COMPARATOR | Participants assigned to the iFIT1 pathway and randomised to this arm will continue standard of care treatment with daratumumab, lenalidomide, and dexamethasone until progressive disease. Dexamethasone may be stopped due to toxicity. |
| iFIT1 - Daratumumab plus teclistamab (Dara-Tec) | EXPERIMENTAL | Participants assigned to the iFIT1 pathway and randomised to this arm will receive treatment with daratumumab and teclistamab for a fixed duration and then be actively monitored until progressive disease. |
| iFIT1 - Daratumumab plus talquetamab (Dara-Tal) | EXPERIMENTAL | Participants assigned to the iFIT1 pathway and randomised to this arm will receive treatment with daratumumab and talquetamab for a fixed duration and then be actively monitored until progressive disease. |
| iFIT2 - DRd to PD | ACTIVE_COMPARATOR | Participants assigned to the iFIT2 pathway and randomised to this arm will continue standard of care treatment with daratumumab, lenalidomide, and dexamethasone until progressive disease. |
| iFIT2 - DR to PD | EXPERIMENTAL | Participants assigned to the iFIT2 pathway and randomised to this arm will continue treatment with daratumumab and lenalidomide until progressive disease. |
| iFIT3 - DR to PD | ACTIVE_COMPARATOR | Participants assigned to the iFIT3 pathway and randomised to this arm will continue treatment with daratumumab and lenalidomide until progressive disease. |
| iFIT3 - DR for 18 cycles | EXPERIMENTAL | Participants assigned to the iFIT3 pathway and randomised to this arm will continue treatment with daratumumab and lenalidomide for 18 cycles, and then be actively monitored until progressive disease. |
| Daratumumab | EXPERIMENTAL | Participants will receive a single dose of daratumumab 16 milligrams per kilograms (mg/kg) intravenous (IV) or 1800 mg subcutaneous (SC) infusion on Cycle 1 Day 1 (28-day cycle), as monotherapy or in combination with standards of care treatment (that is, pomalidomide and dexamethasone, lenalidomide and dexamethasone, carfilzomib and dexamethasone) or standards of care treatment alone, depending on the treatment received in the parent study. Participants who received daratumumab IV during the parent study, will have an option to switch to daratumumab SC on Day 1 of any cycle during this long-term extension study. |
| Arm A: Teclistamab-daratumumab (Tec-Dara) | EXPERIMENTAL | Participants will receive teclistamab and daratumumab by subcutaneous (SC) injection. Step-up doses of teclistamab will be given prior to the first full dose. Participants who are still receiving the treatment and benefiting from it may enter the long-term extension (LTE) and drug access (DA)-LTE Phases to continue their current treatment until end of the study. |
| Arm B: DPd or DVd | EXPERIMENTAL | Participants will be randomized either to daratumumab, pomalidomide, dexamethasone (DPd) treatment to receive daratumumab SC injection; pomalidomide orally; dexamethasone orally or intravenously, or to Daratumumab, Bortezomib, Dexamethasone (DVd) treatment to receive daratumumab SC injection; bortezomib SC injection, and dexamethasone orally or intravenously. Participants randomized to Arm B who do not cross over to Tec-Dara may continue DPd/DVd treatment during the LTE phase. Following the completion of LTE phase, participants who crossed over to Tec-Dara during the LTE may enter the DA LTE and continue to receive study treatment with Tec Dara. Any participants still receiving DPd/DVd at the end of the LTE may not cross over to Tec-Dara and will not continue into the DA-LTE. |
| Daratumumab + Lenalidomide | EXPERIMENTAL | Participants will receive 1800 milligram (mg) daratumumab by subcutaneous (SC) injection in combination with lenalidomide (orally) as maintenance therapy for a maximum of 36 cycles. Each cycle is of 28 days. |
| Lenalidomide | ACTIVE_COMPARATOR | Participants will receive lenalidomide (orally) alone as maintenance therapy for a maximum of 36 cycles. Each cycle is of 28 days. |
| Bortezomib + Lenalidomide + Dexamethasone (VRd) and Rd | ACTIVE_COMPARATOR | Participants will receive bortezomib 1.3 milligram per square meter (mg/m\^2) as subcutaneous (SC) injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9 (cycle of 28 days); dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond (each cycle is of 28 days) followed by lenalidomide-dexamethasone (Rd) until disease progression or unacceptable toxicity. Participants aged greater than (\>)75 years or body mass index (BMI) less than (\<) 18.5 kilograms per meters (kg/m\^2) will receive dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle. |
| Daratumumab + VRd (D-VRd) and DRd | EXPERIMENTAL | Participants will receive daratumumab 1800 mg as SC injection once every week for Cycles 1 to 2, then every 3 weeks for Cycles 3 through 8 and every 4 weeks for Cycle 9 and beyond; bortezomib 1.3 mg/m\^2 as SC injection twice weekly on Days 1, 4, 8, 11 for Cycles 1 through 8 (each cycle is of 21 days); lenalidomide 25 mg orally on Day 1 to Day 14 for Cycles 1 through 8 and on Days 1 to 21 for Cycle 9; dexamethasone 20 mg orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, 12 for Cycles 1 through 8 and 40 mg on Days 1,8, 15 and 22 during Cycle 9 and beyond followed by daratumumab-lenalidomide-dexamethasone (DRd) until disease progression or unacceptable toxicity. Participants aged \>75 years or BMI \<18.5 kg/m\^2 will receive Dexamethasone 20 mg oral tablets on Days 1, 4, 8, and 11 of each cycle. |
| Arm A: Daratumumab, Velcade, and Dexamethasone (DVd) | EXPERIMENTAL | Participants will receive daratumumab weekly for the first 3 cycles, every 3 weeks (q3w) on Day 1 of Cycles 4-9 as an intravenous (IV) infusion at a dose of 16 milligram per kilogram (mg/kg) or will have the option to switch to daratumumab subcutaneously (SC) on Day 1 of any cycle, and then every 4 weeks (q4w) thereafter, Velcade at a dose of 1.3 milligram per square meter (mg/m\^2) subcutaneous (SC) on Days 1, 4, 8 and 11 of each 21-day cycle (up to 8 treatment cycles) and dexamethasone (Dex) orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of the 8 Velcade treatment cycles. |
| Arm B: Velcade and Dexamethasone (Vd) | EXPERIMENTAL | Participants will receive Velcade SC at a dose of 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each 21-day cycle and Dex 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12 (up to 8 cycles). Participants who have sponsor-confirmed disease progression while being treated with Vd or on observation, will be offered the option for treatment with daratumumab monotherapy (16 mg/kg weekly for Cycles 1 and 2, every other week for Cycles 3 to 6, and every 4 weeks for Cycles 7 and onwards until disease progression, unacceptable toxicity, pregnancy, loss of follow-up, withdrawal of consent, or death \[each cycle is 28 days\]), if recommended by the site investigator. |
| CyBorD alone (cyclophosphamide/bortezomib/dexamethasone) | ACTIVE_COMPARATOR | Participants will receive dexamethasone (40 milligrams \[mg\] orally or intravenous \[IV\] dose), followed by cyclophosphamide (300 milligram per meter square \[mg/m\^2\] orally or IV dose), then bortezomib (1.3 mg/m\^2 subcutaneous injection) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. |
| CyBorD plus Daratumumab | EXPERIMENTAL | Participants will receive dexamethasone (20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing) followed by 1800 mg of daratumumab subcutaneously followed by cyclophosphamide (300 mg/m\^2 orally or IV dose weekly) and bortezomib (1.3 mg/m\^2 subcutaneous injection weekly) on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles. Daratumumab will be administered weekly for the first 8 weeks (2 cycles), then every 2 weeks for 4 cycles (cycles 3-6), and then every 4 weeks until progression of disease or subsequent therapy for a maximum of 2 years. |
| Lenalidomide and Dexamethasone (Rd) | ACTIVE_COMPARATOR | Participants will receive Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously once a week. Study treatment continues until disease progression, unacceptable toxicity, or end of study (maximum up to 7 years after last subject is randomized) whichever comes first. |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | ACTIVE_COMPARATOR | Participants will receive Daratumumab 16 milligram per kilogram (mg/kg) by intravenous infusion, once a week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks, Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously once a week. Following implementation of protocol amendment 8, participants still receiving treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion of the investigator. Daratumumab subcutaneous (SC) will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or study completion. Study treatment continues until disease progression, unacceptable toxicity, or end of study (maximum up to 7 years after last subject is randomized) whichever comes first. |
| Daratumumab+VELCADE+dexamethasone | EXPERIMENTAL | Daratumumab, VELCADE and dexamethasone |
| VELCADE+dexamethasone | ACTIVE_COMPARATOR | VELCADE and dexamethasone. |
| Daratumumab + lenalidomide + dexamethasone | EXPERIMENTAL | During each 28-day treatment cycle, participants will receive daratumumab, lenalidomide, and dexamethasone. |
| Lenalidomide + dexamethasone | ACTIVE_COMPARATOR | During each 28-day treatment cycle, participants will receive lenalidomide and dexamethasone. |
| All patients registered in the DALYA trial | EXPERIMENTAL | Treatment consists of an induction phase (every 21 days) planning one course (cycle 1) of daratumumab as single agent followed by 8 courses (cycles 2-9) of daratumumab in combination with bortezomib and dexamethasone (DVd regimen). Patients achieving at least a SD after induction will be addressed to the maintenance phase (every 28 days), planning a maximum of 6 cycles (cycles 10-15) of daratumumab as single agent until disease progression, unacceptable toxicity, withdrawal of consent and/or the investigator decision. |
| Cohort1 (Arm A): Daratumumab + Immediate Cyclophosphamide, Bortezomib and Dexamethasone (VCd) | EXPERIMENTAL | Participants with newly diagnosed systemic amyloid light chain (AL) amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive daratumumab 1800 milligrams (mg) subcutaneously (SC) starting on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square \[mg/m\^2\] either orally or intravenously \[IV\], bortezomib 1.3 mg/m\^2 SC or IV, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22). |
| Cohort1 (Arm B): Daratumumab + Deferred VCd | EXPERIMENTAL | Participants with newly diagnosed systemic AL amyloidosis with Mayo Cardiac Stage II and IIIa cardiac involvement will receive SC daratumumab 1800mg on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (Cyclophosphamide 300 mg/m\^2 either orally or IV, Bortezomib 1.3 mg/m\^2 SC or IV, Dexamethasone 40 mg weekly either orally or IV) starting at Cycle 4 Day 1, weekly (Days 1, 8, 15, 22) in every 28-day cycle for a maximum of 6 cycles (Cycle 9 Day 22). |
| Cohort 2: Daratumumab + VCd | EXPERIMENTAL | Participants with racial and ethnic minorities, including Black or African American participants, with newly diagnosed AL amyloidosis will receive SC injection of daratumumab 1800 mg SC on Day 1 once weekly (q1w) up to Day 22 for cycles 1-2, on Days 1 and 15 for cycles 3-6, and on Day 1 for cycles 7-24 of a 28-day cycle. Participants will also receive VCd (cyclophosphamide 300 milligrams per meter square \[mg/m\^2\] either orally or intravenously \[IV\], bortezomib 1.3 mg/m\^2 SC or IV, dexamethasone 40 mg weekly either orally or IV) weekly starting at Cycle 1 Day 1 up to Day 22 in every 28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22). |
| Daratumumab, Bortezomib,Lenalidomide,Dexamethasone | EXPERIMENTAL | The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Cycle Length is 28 days. The names of the study drugs involved in this study are: * Daratumumab * Bortezomib * Lenalidomide * Dexamethasone |
| Cohort 1: B-Cell Acute Lymphoblastic Leukemia (ALL)/LL | EXPERIMENTAL | Cohort 1 will include participants with B cell ALL/LL in second or greater relapse or refractory to at least 2 prior induction regimens. Participant will receive daratumumab in combination with vincristine and prednisone. |
| Cohort 2: T-Cell ALL/LL | EXPERIMENTAL | Cohort 2 will include participants with T-cell ALL/LL in first relapse or refractory to at least 1 prior induction/consolidation regimen. Participant will receive daratumumab in combination with vincristine, prednisone, doxorubicin and peg-asparaginase in Cycle 1 and daratumumab in combination with cyclophosphamide, cytarabine, 6- mercaptopurine and methotrexate in Cycle 2. |
| Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) | EXPERIMENTAL | Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. |
| D + Bortezomib + Melphalan + Prednisone (D-VMP) | EXPERIMENTAL | Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. |
| Daratumumab + Lenalidomide + Dexamethasone (D-Rd) | EXPERIMENTAL | Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study. |
| Daratumumab + Carfilzomib + Dexamethasone (D-Kd) | EXPERIMENTAL | Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m\^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study. |
| Part 1: JNJ-63723283 + Daratumumab | EXPERIMENTAL | Participants in Safety Run-in cohort will receive daratumumab IV and JNJ-63723283 IV for 1 cycle (28 days). Participants will continue to receive study treatment until confirmed disease progression, unacceptable toxicity, or any other treatment discontinuation criteria are met. Participants who were previously receiving JNJ-283 plus daratumumab have the opportunity to continue daratumumab therapy alone. |
| Part 2 and Part 3: Daratumumab/ JNJ-63723283 + Daratumumab | EXPERIMENTAL | Participants in Treatment Arm A will receive daratumumab IV and in Treatment Arm B will receive daratumumab IV and JNJ-63723283 IV for cycles of 28 days each. All participants will continue to receive study treatment until confirmed disease progression, unacceptable toxicity, or any other treatment discontinuation criteria are met. Participants who were previously receiving JNJ-283 plus daratumumab have the opportunity to continue daratumumab therapy alone. |
| Dara-CyBorD | EXPERIMENTAL | Subjects will receive Daratumumab along with Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) as induction on a 28-day cycle length and Daratumab and Dexamethasone on Day 1 of each cycle for 12 cycles as maintenance therapy. |
| Daratumumab+Lenalidomide+Bortezomib+Dexamethasone (D-RVd) | EXPERIMENTAL | Participants will receive lenalidomide, bortezomib, dexamethasone and daratumumab. |
| Lenalidomide+Bortezomib+Dexamethasone (RVd) | EXPERIMENTAL | Participants will receive lenalidomide, bortezomib and dexamethasone. |
| Arm A (Long Intense) | EXPERIMENTAL | - |
| Arm B (Intermediate) | EXPERIMENTAL | - |
| Arm C (Short Intense) | EXPERIMENTAL | - |
| Part 1 | EXPERIMENTAL | During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants. |
| Part 2 | EXPERIMENTAL | Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2. |
| Experimental | EXPERIMENTAL | Single intravenous infusion of DARATUMUMAB 16 mg/kg body weight. |
| ArmA: Treatment with Subcutaneous Daratumumab Administration in the Anterior Upper Thigh | EXPERIMENTAL | Treatment will be given for 8 weeks. SC Daratumumab will be administered in the thigh weekly for 8 weeks. Patients may receive daratumumab alone or in combination with standard of care regimen |
| ArmB: Treatment with Subcutaneous Daratumumab Administration in the Abdomen | ACTIVE_COMPARATOR | Treatment will be given for 8 weeks. SC Daratumumab will be administered in the abdomen weekly for 8 weeks. Patients may receive daratumumab alone or in combination with standard of care regimen |
| Part 1: Dose Escalation | EXPERIMENTAL | Participants will be assigned to either a combination of 1) daratumumab plus teclistamab or 2) daratumumab plus talquetamab or 3) daratumumab plus talquetamab plus pomalidomide or 4) daratumumab plus teclistamab plus pomalidomide. |
| Part 2: Dose Expansion | EXPERIMENTAL | Participants will be treated with the RP2D(s) for selected treatment combinations determined in Part 1. |
| Placebo | PLACEBO_COMPARATOR | Participants will receive placebo as a single SC dose in each of first 7 cohorts. |
| Part 1: Dose Escalation Part | EXPERIMENTAL | Participants will receive single dose of daratumumab from Week 1 till Week 3 (Period 1 - single dosing period) followed by 6 weekly doses of daratumumab until Week 9 (Period 2 - weekly dosing period) and every 2 weeks for 8 infusions and then once every 4 weeks from Week 26 until disease progression, intolerability, or other reasons for treatment discontinuation (Period 3 - less intense dosing period). A dose of 8 milligram per kilogram (mg/kg) will be chosen as the starting dose and will be escalated to 16 mg/kg if the 8 mg/kg is determined safe and tolerated by study evaluation team (SET). |
| Part 2: Pharmacokinetic (PK) Expansion Part | EXPERIMENTAL | Participants will receive daratumumab at 16 mg/kg in 3 periods as given in the Part 1. |
| Part 3: Safety Expansion Part | EXPERIMENTAL | Participants will receive daratumumab 16 mg/kg every week for 8 weeks followed by every 2 weeks for an additional 16 weeks, and then every 4 weeks thereafter. Participants will be treated with daratumumab until disease progression, intolerability, or any other reasons for treatment discontinuation. |
| Daratumumab with Lenalidomide and dexamethasone | EXPERIMENTAL | Daratumumab (16 milligram per kilogram \[mg/kg\]) will be administered by intravenous \[IV\] infusion to all participants once every week for 8 weeks; then once every other week for 16 weeks; thereafter once every 4 weeks until documented progression, unacceptable toxicity or study end. Participants will receive lenalidomide 25 mg orally on Days 1 through 21 of each 28 day cycle. Participants will receive dexamethasone 40mg weekly, at day 1, 8, 15, 22 of each cycle. |
| Daratumumab 8 milligram per kilogram (mg/kg) | EXPERIMENTAL | Participants will be administered intravenously with daratumumab at a dose of 8 mg/kg up to 8 weeks (total 7 infusions). After 8 weeks, participants will receive daratumumab intravenously two times in every 2 weeks until Week 24 followed by one time in 4 weeks until study discontinuation. |
| Daratumumab 16 mg/kg | EXPERIMENTAL | Participants will be administered intravenously with daratumumab at a dose of 16 mg/kg up to 8 weeks (total 7 infusions). After 8 weeks, participants will receive daratumumab intravenously at a same dose, two times in every 2 weeks until Week 24 followed by one time in 4 weeks until study discontinuation. |
| Daratumumab + VD | EXPERIMENTAL | Daratumumab will be administered with Velcade-dexamethasone (VD). |
| Daratumumab + VMP | EXPERIMENTAL | Daratumumab will be administered with Velcade-melphalan-prednisone (VMP). |
| Daratumumab + VTD | EXPERIMENTAL | Daratumumab will be administered with Velcade-thalidomide-dexamethasone (VTD). |
| Daratumumab + Pom-dex | EXPERIMENTAL | Daratumumab will be administered with pomalidomide-dexamethasone (Pom-dex). |
| Daratumumab + CFZ-dex | EXPERIMENTAL | Daratumumab will be administered with carfilzomib (CFZ)-dexamethasone (CFZ-dex) regimen. |
| Daratumumab + KRd | EXPERIMENTAL | Daratumumab will be administered with carfilzomib- lenalidomide-dexamethasone (KRd) regimen. |
| Name | Type | Description |
|---|---|---|
| Daratumumab | DRUG | Participants will receive daratumumab by subcutaneous injection. Each cycle is 28 days. |
| Lenalidomide | DRUG | Taken orally as capsules. Each cycle is 28 days. Dose can be adjusted for frailty and renal function. |
| Dexamethasone | DRUG | Taken as oral tablets, oral solution, or given by IV. Each cycle is 28 days. Dose can be adjusted for frailty and renal function. |
| Teclistamab | DRUG | Participants will receive teclistamab by subcutaneous injection. Each cycle is 28 days. |
| Talquetamab | DRUG | Participants will receive talquetamab by subcutaneous injection. Each cycle is 28 days. |
| Carfilzomib | DRUG | Carfilzomib will be administered intravenously. |
| Pomalidomide | DRUG | Pomalidomide will be administered orally. |
| Bortezomib | DRUG | Bortezomib will be administered SC injection. |
| Velcade | DRUG | Velcade will be administered at a dose of 1.3 mg/m\^2 SC on Days 1, 4, 8 and 11 of each 21-day cycle. |
| Cyclophosphamide | DRUG | Participants will receive 300 mg/m\^2 of cyclophosphamide as an oral or IV dose. |
| Dexamethasone, 40 mg | DRUG | Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg. |
| Daratumumab IV | DRUG | Daratumumab will be administered at a dose of 16 milligram per kilogram (mg/kg) by intravenous (IV) infusion, once a week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks until documented progression of disease, unacceptable toxicity, or end of study (maximum up to 7 years). |
| Daratumumab SC | DRUG | Daratumumab SC will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or study end. Following implementation of protocol amendment 8, participants still receiving treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion of the investigator. |
| VELCADE (Bortezomib) | DRUG | VELCADE will be administered at a dose of 1.3 mg/m2 subcutaneously (SC) on Days 1, 4, 8 and 11 of each 21-day cycle. Eight VELCADE treatment cycles are to be administered. |
| Vincristine | DRUG | Participant will receive vincristine 1.5 milligram per meter square (mg/m\^2) in cohort 1 and cohort 2. |
| Prednisone | DRUG | Participant will receive prednisone 40 mg/m\^2 in cohort 1 and cohort 2. |
| Doxorubicin | DRUG | Participant will receive doxorubicin 60 mg/m\^2 in cohort 2. |
| Peg-asparaginase | BIOLOGICAL | Participant will receive peg-asparaginase 2500 units per meter square (U/m\^2) in cohort 2. |
| Cytarabine | DRUG | Participant will receive cytarabine 75 mg/m\^2 in cohort 2. |
| 6-mercaptopurine | DRUG | Participant will receive 6-mercaptopurine 60 mg/m\^2 orally daily in cohort 2. |
| Methotrexate | DRUG | Participant will receive methotrexate 5 g/m\^2 intravenously (IV) in cohort 2. |
| Melphalan | DRUG | Melphalan will be administered as 9 mg/m\^2 orally in Cycles 1 to 9. |
| JNJ-63723283 | DRUG | Participants will receive JNJ-63723283 240 mg IV during Week 1 on Cycle 1 Day 2, Cycle 1 Day 15, then every 2 weeks thereafter. |
| Daratumumab 16 mg/kg (Part 1) | DRUG | Daratumumab 16 mg/kg administered at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter by intravenous infusion |
| Daratumumab 8 mg/kg (Part 1) | DRUG | Daratumumab 8 mg/kg every 4 weeks (Q4W) continuously by intravenous infusion |
| Methylprednisolone | DRUG | Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted |
| Acetaminophen | DRUG | 650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration. |
| Diphenhydramine | DRUG | 25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration. |
| Daratumumab (Part 2) | DRUG | Based on the Part 1 response rate, Group A or B treatment will be selected as the treatment regimen for participants enrolled in Part 2. |
| DARATUMUMAB (DARZALEX®) | DRUG | A single injection of DARZALEX 16 mg/kg body weight administered by intravenous infusion (day 1) in addition to standard symptomatic treatment of NET until re-epidermalization. |
| Daratumumab Injection | DRUG | Daratumumab Administration in the Anterior Upper Thigh versus the Abdomen |
| Placebo | DRUG | Placebo liquid will be administered as SC dose in each of first 7 dose cohorts. |
| rHuPH20 | DRUG | Participants in Cohort 8 will receive single SC dose of rHuPH20 as a part of daratumumab formulation. |
| Daratumumab (16 mg/kg) | DRUG | Daratumumab (16 mg/kg) will be administered by IV infusion to all participants once every week for 8 weeks; then once every other week for 16 weeks; thereafter once every 4 weeks until documented progression, unacceptable toxicity or study end. |
| Thalidomide | DRUG | Administered orally in accordance with product labeling and local standards. |
| Montelukast | DRUG | Administered intravenously or orally only with the first daratumumab dose in accordance with product labeling and local standards. |
Eligibility criteria for registration: Inclusion criteria for registration: 1. Newly diagnosed as having symptomatic MM, plasma cell leukaemia or non-secretory MM according to IMWG diagnostic criteria 2014. 2. Considered not suitable to receive autologous stem cell transplant as part of their firs...