Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication DARZALEX is indicated for the treatment of adult patients with 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. FDA label
Also known as Daratumumab SC, Daratumumab Injection, Daratumumab IV, DARATUMUMAB (DARZALEX®), Daratumumab (Subcutaneously), Dara, JNJ-54767414, Darzalex Faspro
Daratumumab · 58 trials · 37 indications
The proportion of participants achieving measurable residual disease negativity at a sensitivity level of 10\^-5 together with complete response, assessed according to International Myeloma Working Group (IMWG) criteria at the specified timepoint.
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.
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) 2016 response criteria, or death due to any cause, whichever occurs first.
Severity for CRS will be graded as follows: Grade 1: Fever (Temperature greater than or equal to \[\>=\] 38°C); Grade 2: Fever (Temperature \>=38°C) with either: hypotension and/or hypoxia requiring low-flow nasal cannula or blow-by; Grade 3: Fever (Temperature \>=38°C) with either: hypotension and/or hypoxia requiring high-flow nasal cannula, facemask, nonrebreather mask, or Venturi mask; Grade 4: Fever (Temperature \>=38°C) with either: hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia requiring positive pressure and Grade 5: Death.
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 duration from the date of randomization to either progressive disease or death, whichever comes first. Disease progression will be determined according to the International Myeloma Working Group (IMWG) response criteria.
12-month MRD-negative CR is defined as participants who achieve MRD-negative status at 12 months, as determined by next-generation sequencing (NGS) with sensitivity of 10\^-5, prior to progressive disease or subsequent anti-myeloma therapy and who also achieve CR or better, according to IMWG criteria.
Will be estimated using the Kaplan-Meier (KM) method and compared using a stratified log-rank test. Stratified cox proportional hazards regression will produce a treatment hazard ratio estimate.
A general effect size measure of half standard deviation will be used to establish the minimally important difference. Descriptive statistics (mean, standard deviation \[SD\], median, range) will be used to evaluate the distribution of levels and changes for the set of health-related quality of life (QOL) evaluations. Levels and changes will also be assessed graphically. Changes from baseline will be analyzed using linear mixed models based on restricted maximum likelihood estimation with covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. If there is substantial missingness, will analyze the data according to the methods described in Schluchter and Schluchter, Greene and Beck.
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).
ORR was defined as the percentage of participants who achieved partial response (PR) or better according to International Myeloma Working Group (IMWG) criteria, during or after study treatment. 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)/24 hours, If the serum and urine M-proteins are not measurable, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels were required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay was also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) was 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 was also required.
Maximum Ctrough was defined as the serum predose concentration of daratumumab on Cycle 3 Day 1.
to determine the Complete Response Rate (CRR), defined as the proportion of subjects achieving complete response (CR) or stringent complete response (sCR) according to IMWG criteria at the 'Pre-Maintenance' timepoint (after completion of Immunotherapy #4, Cycle 4)
determine the 2-year Progression-Free Survival (PFS) percentage in subjects with high-risk multiple myeloma (HRMM) treated with the sequential use of bispecific antibodies.
Overall immunoglobulin M (IgM) efficacy will be evaluated by assessing the IgM response rate and the objective response rate (ORR, PR or better; at least 25% improvement in IgM from baseline). Overall response rate (ORR) includes patients who achieved minor response (MR), partial response (PR), very good partial response (VGPR), and complete response (CR). Response rates will be presented with exact 95% confidence intervals. With 24 patients, there is 99% power to reject a null rate of IgM response of 0.30 assuming an alternative IgM response rate of 0.70 based on the exact binomial exact test with a one-sided significance level of 0.03. The alternative IgM response rate will be rejected if at least 12 of 24 patients have a response.
Heme-CR will be defined as: involved free light-chain level less than the upper limit of the normal range with negative serum and urine immunofixation; normalization of the uninvolved free light-chain level or free light-chain ratio will not be required to determine a complete response.
Percentage of participants achieving CR or better according to EHA/ISA guidelines
Complete renal remission (proteinuria \<500 mg/d and \<15% decline in baseline eGFR) Partial renal remission (\>50% reduction in 24-h proteinuria and \< 30% decline in eGFR)
Evaluate the overall incidence of CRS in the first 2 cycles after a single dose of prophylactic tocilizumab given 2 to 4 hours prior to step-up dose 1 of teclistamab or talquetamab or after 3 doses of oral dexamethasone given after each step-up dose and the first full dose of teclistamab.
Requires that all of the following be present. * Peripheral Blood Counts * Neutrophil count ≥ 1,000/µL. * Platelet count ≥ 100,000/µL. * Reduced hemoglobin concentration or hematocrit has no bearing on remission status. * Leukemic blasts must not be present in the peripheral blood. * Bone Marrow Aspirate and Biopsy * Cellularity of bone marrow biopsy must be \> 20% with maturation of all cell lines. * ≤ 5% T lymphoblasts by flow cytometry. * Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present.
The same as for CR except with unsupported platelets \> 50,000/μL, hemoglobin \> 7 g/dL, and absolute neutrophil count \> 500/μL.
All the same response criteria in peripheral blood and bone marrow as CR with the exception that there is incomplete platelet recovery (platelets \> 75,000/uL but \< 100,000/μL independent of platelet transfusions) or incomplete neutrophil count recovery \> 750/uL but \< 1000/μL.
Bone marrow lymphoblast percent \< 0.01% (\< 10-4) by flow cytometry in a patient that fulfills count requirements for CR/CRh/CRi..
Bone Marrow Aspirate and Biopsy * Presence of \> 5% T lympho-blasts, not attributable to another cause (e.g., bone marrow regeneration). * If there are no circulating blasts and the bone marrow contains 5% to 20% blasts, then a repeat bone marrow performed ≥ 1 week later documenting more than 5% blasts is necessary to meet the criteria for relapse.
• Relapse following MRD negativity is defined as bone marrow T lymphoblast percent ≥ 0.01% (10-4).
Failure to achieve MRD negativity as defined by bone marrow with CR/CRh/CRi with T lymphoblast percent ≥ 0.01% (10-4).
The complete response rate (CRR) was defined as the proportion of participants achieving complete response (CR) based on International Myeloma Working Group (IMWG) Response criteria. CR defined as requires all of the following: * Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of six weeks by immunofixation studies. * \<5% plasma cells in the bone marrow on at least two determinations for a minimum of six weeks. * No increase in the size or number of lytic bone lesions (development of a compression fracture does not exclude response). * Disappearance of soft tissue plasmacytomas for at least six weeks.
Levels of HLA titers by measure of fluorescence intensity levels (MFI) of donor specific antibodies (DSA).
Assessed as calculated panel of reactive antibodies (cPRA) and absolute HLA antibody levels (MFI)
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
Of participants who complete at least one cycle of induction therapy, proportion that achieve MRD-negativity after completion of induction + those who achieve MRD-negativity after completion of consolidation (if still MRD-positive after induction). MRD status determined by International Myeloma Working Group (IMWG) Response Criteria.
ORR is defined as the proportion of participants who have a partial response (PR) or better according to the International Myeloma Working Group (IMWG) criteria.
The primary comparison across the two treatment arms will use a mixed effects linear regression model.
Overall Response Rate of the response adapted strategy using the uniform response criteria of the International Myeloma Working Group (IMWG). Stringent Complete Response (sCR): Below plus normal FLC ratio and absence of clonal cells in bone marrow3 by immunohistochemistry or immunofluorescence Complete Response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \> 90% reduction in serum M-protein plus urine M-protein level \< 100 mg/24 h Partial Response (PR): \> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>90% or to \< 200 mg/24 h Minimal Response (MR): 25%-49% reduction of serum M-protein and 50%-89% reduction in 24 hours urinary M-protein Stable Disease (SD): Not meeting criteria for sCR, CR, VGPR, PR, MR, or Progressive Disease (PD)
≥ VGPR rate after 8 cycles of therapy, defined as the proportion of subjects who have achieved VGPR or better, according to the IMWG criteria.
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 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.
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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.
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.
Cmax is defined as the maximum observed serum concentration of teclistamab (after first treatment dose).
AUCtau is defined as area under the concentration-time curve during dosing interval of teclistamab (after first treatment dose).
Ctrough is defined as observed serum concentration immediately prior to the next study treatment administration.
An AE can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product.
Number of participants with AEs by severity will be reported.
Number of participants with abnormalities in laboratory values (such as serum chemistry, hematology) will be reported.
The Dose Limiting Toxicities (DLTs) are based on drug related adverse events and defined as any of the following events: hematological / non hematological toxicity of Grade 3 or higher.
An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non investigational) product.
A SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a suspected transmission of any infectious agent via a medicinal product; is medically important.
Number of participants with DLT will be assessed. The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity.
ORR is defined as the percentage of participants who have a partial response (PR) or better according to the 2016 International Myeloma Working Group (IMWG) response criteria.
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.
An adverse event (AE) is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.
The Dose Limiting Toxicities (DLTs) are based on drug related adverse events and defined as any of the following events: hematological / non hematological toxicity of Grade 3 or higher.
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
ORR was defined as the percentage of participants with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Criteria for CR: Disappearance of all target lesions; all lymph nodes must be of non-pathological in size (less than \[\<\]10 millimeter \[mm\] short axis; normalization of tumor marker level. Criteria for PR: greater than or equal to (\>=)30 percent (%) decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. Overall Response (OR) = CR + PR. The outcome measure (OM) was planned to be reported for participants based on their initial assignment to Randomized Phase: Atezolizumab'.
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.
An AE was 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. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
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.
ORR is defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). International Myeloma Working Group (IMWG) criteria (2011)- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than (\<) 5 percentage (%) plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immuno fluorescence; PR: greater than equal to (\>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>= 90 percentage (%) or to \<200 mg/24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour.
ORR is defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). IMWG criteria (2011)- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than (\<) 5 percentage (%) plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; PR: greater than eqaul to (\>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>= 90 percentage (%) or to \<200 mg/24 hours; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour.
Efficacy as assessed by the percentage of patients with DSA levels that are reduced to a level permissible for RIC alloHSCT with DSA strength of II or less and at least a 10% decrease in MFI from the baseline as determined by the JH-DSA Response Score.
Proportion of patients with Grade 3 or higher toxicities attributable to daratumumab for one cycle of Darzalex Faspro
| Arm | Type | Description |
|---|---|---|
| Arm A (Tec-Tal) | EXPERIMENTAL | Participants receive maintenance therapy with teclistamab in combination with talquetamab. The study evaluates whether maintenance treatment with dual immunotherapy can improve eradication of measurable residual disease in participants with newly diagnosed multiple myeloma who remain MRD-positive after autologous stem cell transplantation. Treatment is administered according to protocol-defined procedures, and participants are followed for assessment of efficacy and safety outcomes. |
| Arm B (Dara-R) | ACTIVE_COMPARATOR | Participants receive maintenance therapy with daratumumab and lenalidomide. This treatment regimen represents the comparator maintenance strategy for participants with newly diagnosed multiple myeloma who remain MRD-positive after autologous stem cell transplantation. Treatment is administered according to protocol-defined procedures, and participants are followed for assessment of efficacy and safety outcomes. |
| 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. |
| Teclistamab | EXPERIMENTAL | Participants will receive teclistamab monotherapy in Part 1 and an alternative dosing regimen of teclistamab in Part 2. |
| Pomalidomide, Bortezomib and Dexamethasone (PVd) or Carfilzomib and Dexamethasone (Kd) | EXPERIMENTAL | Participants will receive either PVd or Kd based on principal investigator's choice during Part 1 of the study. |
| 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. |
| Teclistamab, Daratumumab SC, and Lenalidomide (Tec-DR) | EXPERIMENTAL | Participants will receive teclistamab as subcutaneous (SC) injection in combination with daratumumab and lenalidomide. |
| Talquetamab, Daratumumab SC, and Lenalidomide (Tal-DR) | EXPERIMENTAL | Participants will receive talquetamab as SC injection in combination with daratumumab and lenalidomide. |
| Daratumumab SC, Lenalidomide, and Dexamethasone (DRd) | ACTIVE_COMPARATOR | Participants will receive daratumumab as SC injection with lenalidomide and dexamethasone. |
| 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. |
| Arm I (daratumumab, lenalidomide, dexamethasone) | EXPERIMENTAL | Patients receive daratumumab IV on days 1, 8, 15, and 22 of courses 1-2, days 1 and 15 of courses 3-6, and day 1 of courses 7-24. Patients also receive lenalidomide PO daily on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22 in courses 1-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. |
| Arm II (lenalidomide, dexamethasone) | EXPERIMENTAL | Patients receive lenalidomide PO daily on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22 of courses 1-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. |
| 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. |
| Dara SC | EXPERIMENTAL | Participants will receive a fixed dose of daratumumab as 1800 milligram (mg) subcutaneously (Dara SC) co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Unit per milliliter (U/mL), once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. The duration for each cycle is 4 weeks. |
| Dara IV | ACTIVE_COMPARATOR | Participants will receive daratumumab for intravenous infusion (Dara IV) 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks on Day 1 in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. The duration for each cycle is 4 weeks. For Participants still receiving treatment with Dara-IV at the time of Protocol Amendment 4 the duration of infusion may be shortened to a 90-minute infusion or participants will have the option to switch to Dara 1800 mg subcutaneous (SC) on Day 1 of any cycle, at the discretion of the investigator. |
| 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. |
| MRD-negative | EXPERIMENTAL | Subjects who are MRD-negative (a threshold of 10\^5) will be given teclistamab+daratumumab followed by talquetamab+daratumumab each for 4 cycles followed by 2-year fixed duration treatment with daratumumab and lenalidomide extended/maintenance therapy for a maximum of 24 cycles, or until myeloma progression. |
| MRD-positive | EXPERIMENTAL | Subjects who are MRD-positive (a threshold of 10\^5) will receive a single melphalan (MEL)-based hematopietic stem cell transplantation (HSCT) followed by teclistamab+daratumumab followed by talquetamab+daratumumab each for 4 cycles followed by a 2-year fixed duration treatment with daratumumab and lenalidomide extended/maintenance therapy for a maximum of 24 cycles, or until myeloma progression. MRD status with classification threshold of 10\^5 will be assessed by standardized flow cytometry. |
| Teclistamab-Daratumumab | EXPERIMENTAL | All participants in this study will receive teclistamab and daratumumab. |
| Daratumumab as a single agent therapy | ACTIVE_COMPARATOR | Daratumumab |
| Daratumumab combined with stem cell transplantation | ACTIVE_COMPARATOR | Daratumumab in combination with stem cell transplantation |
| Tec-Dara | EXPERIMENTAL | For patients assigned to cohort A (Tec-Dara) patients will receive Tec-Dara until documented PD or unacceptable toxicity |
| Tec-Len | EXPERIMENTAL | For patients assigned to cohort B (Tec-Len) patients will receive Tec-Len until documented PD or unacceptable toxicity |
| Teclistamab/Tocilizumab | EXPERIMENTAL | Participants will receive step up dosing of Teclistamab following the recommended dosage of TECVAYLI™ USPI followed by weekly dosing for twelve 28-day cycles, until disease progression, unacceptable toxicity, or the EOT (end of Cycle 12). Teclistamab dosing may be reduced to once every 2 weeks for participants who achieve partial response (PR) or better after 6 months of therapy. |
| Talquetamab/Tocilizumab | EXPERIMENTAL | Participants will receive step up dosing of Talquetamab following the recommended dosage of TALVEY™ USPI followed by every 2 week dosing for six 28-day cycles, until disease progression, unacceptable toxicity, or the EOT (end of Cycle 6). Talquetamab dosing may be reduced to once every 4 weeks for participants who achieve very good partial response (VGPR) or better after Cycle 4. Participants in the talquetemab arm cannot be re-screened for or re-enrolled into the teclistamab arm. |
| Teclistamab/Oral Dexamethasone | EXPERIMENTAL | Participants will receive step-up dosing of Teclistamab followed by weekly dosing for two cycles, every other week during Cycles 3-6 and once every 4 weeks from Cycles 7 through 12 until disease progression, unacceptable toxicity, or the EOT (end of Cycle 12). Teclistamab dosing may be reduced to once every 4 weeks for participants who achieve very good partial response (VGPR) or better starting with Cycle 3. |
| Course 1 | EXPERIMENTAL | Daratumumab-hyaluronidase |
| Lenalidomide + Dexamethasone (LD) | ACTIVE_COMPARATOR | Each study treatment cycle lasts 28 days. Participants will be randomized into either Teclistamab arm or Lenalidomine + Dexamethoasone arm * Lenalidomine * Dexamethoasone |
| 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. |
| HLA Desensitization Group | EXPERIMENTAL | Subjects awaiting cardiac transplantation with high levels of circulating Human Leukocyte Antigen (HLA) antibodies will receive daratumumab/hyaluronidase-fihj. |
| 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 |
| Dara-Rd followed by Dara-RVd | EXPERIMENTAL | * Induction regimen with Daratumumab, Lenalidomide and Dexamethasone (Dara-Rd) in all study subjects, weeks 1-24 * Consolidation regimen with Daratumumab, Lenalidomide, Bortezomib and Dexamethasone (Dara-RVd) in post-induction MRD+ population, weeks 25-36 * Maintenance regimen with Daratumumab and Lenalidomide (Dara-R) in all study subjects, weeks 37-88 * Maintenance regimen with lenalidomide (R) until progression or intolerance |
| Part 3: Teclistamab | EXPERIMENTAL | Participants will receive teclistamab subcutaneously (SC) at recommended Phase 2 dose (RP2D) in Cohort A and Cohort C. |
| Lenalidomide maintenance | EXPERIMENTAL | Arm A: Those randomized to lenalidomide maintenance will receive a maintenance dose of 10mg oral lenalidomide on days 1-21 of each 28-day cycle. HRQoL with EORTC QLQ-C30, EORTC QLQ-MY20 and PRO-CTCAE questionnaires will be collected: prior to therapy initiation (baseline); day 1 of cycle 2 and every cycle day 1 thereafter; at therapy discontinuation, and at 1-month post therapy follow-up. Sub ARM A: The first 15 patients on each arm interested in this sub study will be enrolled during C10D1 visit to initiate whole food plant based diet (WFPBD) meals provided by Daily Harvest and nutrition counseling for 12 weeks. They will continue on their lenalidomide maintenance schedule per study calendar. The patients who do not go on the nutrition sub study will continue on their lenalidomide maintenance schedule per study calendar. |
| Daratumumab maintenance | EXPERIMENTAL | ARM B: Those randomized to receive daratumumab maintenance will receive 1800 milligrams (mg) subcutaneous (SC) injection of daratumumab as follows: days 1, 8, 15, and 22 of cycles 1 and 2; days 1 and 15 of cycles 3-6; day 1 of cycles 7-36. HRQoL with EORTC QLQ-C30, EORTC QLQ-MY20 and PRO-CTCAE questionnaires will be collected: prior to therapy initiation (baseline); day 1 of cycle 2 and every cycle day 1 thereafter; at therapy discontinuation, and at 1-month post therapy follow-up. Sub ARM B: The first 15 patients on each arm interested in this sub study will be enrolled during C10D1 visit to initiate whole food plant based diet (WFPBD) meals provided by Daily Harvest and nutrition counseling for 12 weeks. They will continue on their daratumumab maintenance schedule per study calendar. The patients who do not go on the nutrition sub study will continue on their daratumumab maintenance schedule per study calendar. |
| A: Daratumumab & Dexamethasone | EXPERIMENTAL | All participants will receive 1800 mg in 15 ml Daratumumab by subcutaneous injection weekly and be given 20 mg of Dexamethasone orally once a week for 2 months. Patients who receive a partial response or better will continue on this arm. |
| B: Daratumumab, Dexamethasone and Lenalidomide | EXPERIMENTAL | Participants who have less than a partial response to Arm A may have Lenalidomide added to their treatment. Lenalidomide will be given orally on days 1-21 of each 28 day treatment cycle. |
| C: Daratumumab, Dexamethasone and Bortezomib | EXPERIMENTAL | Participants who have less than a partial response to Arm A may have Bortezomib added to their treatment. Bortezomib will be given weekly in subcutaneous injections at a starting dose of 1/3 mg/m\^2 Days 1,8 and 15 of each 28 day treatment cycle. |
| Daratumumab with dose-attenuated VRd | EXPERIMENTAL | SubQ Daratumumab with Dose-Attenuated VRd |
| 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. |
| Study Treatment | EXPERIMENTAL | Induction Chemotherapy: Carfilzomib, Thalidomide, Dexamethasone, Daratumumab , CisPlatin, Adriamycin, Cyclophosphamide and Etoposide (KTD-Dara-PACE). Autologous Stem Cell Transplant (ASCT) 1: Melphalan, Dexamethasone, ASCT. Immunological Consolidation 1: Daratumumab. Consolidation 1: Daratumumab, Carfilzomib, Dexamethasone (Dara-KD). ASCT 2 (optional): Melphalan, Dexamethasone, ASCT. Immunological Consolidation 2: Daratumumab. Maintenance: Dara-KD alternating with Daratumumab, lenalidomide, and Dexamethasone (Dara-RD) in 3-month blocks. Bortezomib may be substituted for carfilzomib throughout the regimen at the discretion of the treating physician. |
| 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. |
| 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. |
| Dose Escalation: Daratumumab | EXPERIMENTAL | - |
| Dose Expansion: Daratumumab | EXPERIMENTAL | - |
| 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 |
| Arm A: Pre-change Teclistamab | EXPERIMENTAL | Participants will receive teclistamab monotherapy (made from the pre-change manufacturing process) for all step-up and treatment doses until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent to treatment, or end of the study, whichever occurs first. Following completion of the planned analysis per protocol, approval of Amendment 3, and upon sponsor notification, participants from treatment phase will be transitioned to Drug Access Long-term Extension (DA-LTE) phase and will continue to receive the study treatment until they have either discontinued, withdrawn, or transitioned to one of the criteria specified in the protocol. Based on primary analysis demonstrating comparability between pre- and post-change teclistamab, flexibility has been introduced to allow participants to switch from their current teclistamab treatment, if necessary. |
| Arm B: Post-change Teclistamab | EXPERIMENTAL | Participants will receive teclistamab monotherapy (made from the post-change manufacturing process) for all step-up and treatment doses until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent to treatment, or end of the study, whichever occurs first. Following completion of the planned analysis per protocol, approval of Amendment 3, and upon sponsor notification, participants from treatment phase will be transitioned to DA-LTE phase to receive the study treatment until they have either discontinued, withdrawn, or transitioned to one of the criteria specified in the protocol. Based on primary analysis demonstrating comparability between pre- and post-change teclistamab, flexibility has been introduced to allow participants to switch from their current teclistamab treatment, if necessary. |
| Treatment Regimen A: Teclistamab + Daratumumab + Pomalidomide | EXPERIMENTAL | Participants will receive teclistamab plus daratumumab plus pomalidomide. |
| Treatment Regimen B: Teclistamab + Daratumumab + Lenalidomide + Bortezomib (21-day Cycles) | EXPERIMENTAL | Participants will receive teclistamab plus daratumumab plus lenalidomide plus bortezomib in 21-day cycles. |
| Treatment Regimen C: Teclistamab + Nirogacestat | EXPERIMENTAL | Participants will receive teclistamab plus nirogacestat. |
| Treatment Regimen D: Teclistamab + Lenalidomide | EXPERIMENTAL | Participants will receive teclistamab plus lenalidomide. |
| Treatment Regimen E: Teclistamab + Daratumumab + Lenalidomide | EXPERIMENTAL | Participants will receive teclistamab plus daratumumab plus lenalidomide. |
| Treatment Regimen F: Teclistamab + Daratumumab + Lenalidomide + Bortezomib (28-day Cycles) | EXPERIMENTAL | Participants will receive teclistamab plus daratumumab plus lenalidomide plus bortezomib in 28-day cycles. |
| Japanese Participants with Relapsed or Refractory Multiple Myeloma (MM) | EXPERIMENTAL | Japanese participants will receive Teclistamab subcutaneously (SC) at four dose levels. Cohort 1 will receive Teclistamab at Dose 1 and 2 (step-up doses) prior to first treatment dose on Day 1 followed by Dose 3 weekly (that is, on Days 1,8, and 15 of a 21-day cycle). Cohort 2 will receive Teclistamab at Dose 1 and 4 (step up doses) prior to first treatment dose on Day 1 followed by Dose 5 weekly. Cohort 3 will receive Teclistamab at Dose 1, 4, and 5 (step up doses) prior to first treatment dose on Day 1 followed by Dose 6 weekly. Cohort 4 will receive Teclistamab at Dose 1, 4, and 5 (step up doses) prior to first treatment dose on Day 1 followed by Dose 7 weekly for (2 cycles), then biweekly (cycle 3 to 6) on Days 1 and 15 and monthly (cycle 7) on Day 1 of 1 28-day cycle. In Phase 2 , participants will receive Teclistamab SC at Dose 1 and 4 (step up doses) up to 8 days prior to first treatment dose on Day 1 followed by Dose 5 on Days 1,8,15, and 22 of a 28-day cycle. |
| 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. |
| Part 1: Dose Escalation (IV) | EXPERIMENTAL | Participants will receive Teclistamab intravenously (IV). |
| Part 2: Dose Expansion (IV) | EXPERIMENTAL | Participants will receive Teclistamab IV. |
| Part 1: Dose Escalation (SC) | EXPERIMENTAL | Participants will receive Teclistamab subcutaneously (SC). |
| Part 2: Dose Expansion (SC) | EXPERIMENTAL | Participants will receive Teclistamab SC. |
| Treatment Arm A: Atezolizumab | EXPERIMENTAL | Participants in Treatment Arm A will receive Atezolizumab 1,200 milligram (mg) intravenously (IV) on Day 1 of every 21-day cycle. Participants with confirmed disease progression based on RECIST 1.1 may cross over to Arm B and receive daratumumab and atezolizumab, provided crossover eligibility criteria are met. |
| Treatment Arm B: Atezolizumab and Daratumumab | EXPERIMENTAL | Participants will receive daratumumab 16 milligram per kilogram \[mg/kg\] (Safety Run-in and Treatment Arm B) Intravenously (IV) weekly for 3 cycles (Day 1, 8 and 15), and Day 1 of every 21-day cycle thereafter. Atezolizumab will be administered at 1200 mg IV on Day 2 of Cycle 1 and on Day 1 of every 21-day cycle thereafter. Participants will continue to receive study treatment until confirmed disease progression, unacceptable toxicity, or any other treatment discontinuation criteria are met. |
| 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. |
| JNJ-54767414 (Daratumumab) +Bortezomib+Dexamethasone | EXPERIMENTAL | Participants will be administered JNJ-54767414 (daratumumab) intravenously at a dose of 16 milligram per kilogram (mg/kg) weekly for the first 3 cycles, then on Day 1 of Cycles 4-8 (every 3 weeks), and then on Day 1 of subsequent cycles (every 4 weeks), First 8 Cycles are 21-day cycles; Cycles 9 and onwards are 28-day cycles. Bortezomib at a dose of 1.3 milligram per meter square (mg/m\^2) subcutaneously (SC) on Days 1, 4, 8 and 11 of each 21-day cycle for 8 treatment cycles and Dexamethasone orally at 20 mg on Day 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 bortezomib treatment cycles. |
| 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. |
| Daratumumab-SC followed by standard of care DSA desensitization and alloBMT | EXPERIMENTAL | Darzalex Faspro (Daratumumab and hyaluronidase-fihj) will be administered subcutaneously (SC) weekly (every 7 day +/- 1 day) for a total of four doses followed by standard desensitization regimen and allogeneic stem cell transplant. |
| Name | Type | Description |
|---|---|---|
| Teclistamab | DRUG | Teclistamab is administered as part of combination immunotherapy according to protocol-defined dosing and schedule in participants receiving maintenance treatment for multiple myeloma. |
| Talquetamab | DRUG | Talquetamab is administered in combination with teclistamab as part of maintenance immunotherapy according to protocol-defined dosing and schedule. |
| Daratumumab (Subcutaneously) | DRUG | Daratumumab is administered as part of standard maintenance therapy according to protocol-defined dosing and schedule in participants with multiple myeloma. |
| Lenalidomide | DRUG | Lenalidomide is administered as continuous maintenance therapy according to protocol-defined dosing and schedule in combination with daratumumab. |
| Daratumumab | DRUG | Participants will receive daratumumab by subcutaneous injection. Each cycle is 28 days. |
| 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. |
| Pomalidomide | DRUG | Pomalidomide will be administered orally. |
| Bortezomib | DRUG | Bortezomib will be administered subcutaneously. |
| Carfilzomib | DRUG | Carfilzomib will be administered intravenously. |
| Quality-of-Life Assessment | OTHER | Ancillary studies |
| Questionnaire Administration | OTHER | Ancillary studies |
| 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. |
| Dara SC | DRUG | Participants will receive a fixed dose of Dara SC as 1800 mg daratumumab with rHuPH20 2000 U/mL, once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. |
| Dara IV | DRUG | Participants will receive Dara IV 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. |
| 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. |
| teclistamab+daratumumab followed by talquetamab+daratumumab followed by duration treatment with daratumumab and lenalidomide extended/maintenance | DRUG | teclistamab+daratumumab followed by talquetamab+daratumumab each for 4 cycles followed by 2-year fixed duration treatment with daratumumab and lenalidomide extended/maintenance therapy for a maximum of 24 cycles, or until myeloma progression. |
| melphalan (MEL)-based hematopietic stem cell transplantation (HSCT) followed by drug therapy | PROCEDURE | Subjects who are MRD-positive (a threshold of 10\^5) will receive a single melphalan (MEL)-based hematopietic stem cell transplantation (HSCT) followed by teclistamab+daratumumab followed by talquetamab+daratumumab each for 4 cycles followed by a 2-year fixed duration treatment with daratumumab and lenalidomide extended/maintenance therapy for a maximum of 24 cycles, or until myeloma progression. |
| Daratumumab and Hyaluronidase-fihj | DRUG | Daratumumab is an monoclonal antibody that targets the CD38 protein on the surface of myeloma cells. |
| Tocilizumab | DRUG | Tocilizumab will be administered as a pretreatment medication in advance of administration of the first step-up dose of teclistamab or talquetamab on Cycle 1 Day 1. |
| Oral Dexamethasone | DRUG | Oral dexamethasone will be administered as a pretreatment medication every 12 hours in 3 doses (PM/AM/PM) following each step-up dose and the first full dose of teclistamab in Cycle 1. A total of 9 doses of oral dexamethasone will be administered. |
| Daratumumab / Hyaluronidase Injection | DRUG | Daratumumab-hyaluronidase 1800mg/ 30,000 units once weekly for 4 doses on Days 1, 8, 15, and 22 |
| Cyclophosphamide | DRUG | Cyclophosphamide will be administered either orally or IV. |
| Questionnaires | BEHAVIORAL | EORTC QLQ-C30, EORTC QLQ-MY20, PRO-CTCAE) |
| Dietary Intervention | OTHER | The intervention, consisting of fully prepared whole foods plant based (WFPBD) meals and behavioral coaching provided by Daily Harvest. Patients receive self-selected WFPBD meals (lunch/dinner) for 12 weeks, along with guidance for snacks and breakfast. Behavioral counseling will be provided by health coaches and a research dietitian. The first 15 participants on each arm interested in this intervention will be enrolled on C13D1 or C25D1. |
| Daratumumab Injection | DRUG | Patient will receive daratumumab (1800 mg in 15 ml) administered by manual subcutaneous injections weekly for the first 8 weeks, every other week for the next 16 weeks and every 4 weeks after. |
| Dexamethasone Oral | DRUG | The dexamethasone starting dose will be 20 mg PO once a week. Commercial dexamethasone will be used. Dexamethasone is often supplied in 4 mg tablets. Accordingly, patients will take 5 (4 mg tablets) one day of the week prior to the administration of daratumumab if this corresponds to a daratumumab dosing days. In non daratumumab dosing days, dexamethasone will be taken by the patient at home, usually in the morning with breakfast. |
| Lenalidomide Pill | DRUG | Lenalidomide will be given orally on days 1-21 of a 28 days cycle. The starting dose of lenalidomide will be based on the patient creatinine clearance per the package insert. Specifically patients with a creatinine clearance ≥ 50 ml/min will receive 25 mg of lenalidomide PO Days 1-21. Patients with a creatinine clearance ≥ 30 but less than 50 ml/min will receive 10 mg of lenalidomide. Patients with a creatinine clearance \< 30 ml/min are not eligible but patients who experience a deterioration in the renal function during screening or treatment may continue on lenalidomide therapy as long as the risk / benefit profile is deemed acceptable, that study therapy is in the best interest of the patient and after discussion with the study principal investigator / sponsor. |
| Bortezomib Injection | DRUG | Bortezomib will be given weekly subcutaneously in an effort to decrease the toxicity of the therapy. Specifically patients will receive a starting dose of bortezomib of 1.3 mg/m\^2 Days 1,8,15 of a 28 day cycle. Bortezomib will be administered in the cancer center per standard of care procedures. |
| Ixazomib | DRUG | During maintenance treatment, if choice of maintenance therapy includes ixazomib, ixazomib will be administered at 3 mg orally daily on Days 1,8, and 15 of each cycle. For subjects with CrCl 15-30 mL/min, ixazomib will be reduced to 2.3 mg once per week during maintenance treatment. |
| 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. |
| Thalidomide | DRUG | Given by mouth at bedtime: days 1-4 of Induction |
| Cisplatin | DRUG | Given by vein: days 1-4 (continuous infusion) of Induction |
| Adriamycin | DRUG | Given by vein: days 1-4 (continuous infusion) of Induction |
| Etoposide | DRUG | Given by vein: days 1-4 (continuous infusion) of Induction |
| ASCT | PROCEDURE | day 0 of Transplant(s) |
| 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. |
| Part 1: Daratumumab | DRUG | First participant will receive intravenous (injection of a substance into a vein) 0.005 milligram per kilogram (mg/kg) (planned dose) infusion of daratumumab and other participants will receive different doses. The participants will receive 7 full infusions of daratumumab and 2 predose infusions every 2 weeks. The dose of daratumumab will be escalated sequentially and considering the safety and efficacy of dose in Part 1, dose for Part 2 of the study will be decided. A predose infusion of 10% of the full dose of daratumumab will be administered a day before the first 2 full infusions. |
| Part 2: Daratumumab | DRUG | In Part 2, the participants will receive dose of daratumumab as determined in part 1 (16 mg/kg) of the study. Participants will receive 8 full infusions at weekly intervals followed by biweekly (every 2 weeks) infusions for 16 additional weeks and monthly infusions until disease progression or unmanageable toxicity, whichever comes first. Predose was dropped at some point in Part 2. A predose infusion of 10 mg daratumumab will be administered on the day before the first full infusion in select cohorts. |
| 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. |
| Nirogacestat | DRUG | Participants will receive nirogacestat. |
| Teclistamab (IV) | DRUG | Participants will receive IV infusion of Teclistamab. |
| Teclistamab(SC) | DRUG | Participants will receive SC injection of Teclistamab. |
| Atezolizumab | DRUG | Participants will receive atezolizumab 1200 mg intravenously. |
| 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. |
| JNJ-54767414 (Daratumumab) | DRUG | JNJ-54767414 (Daratumumab) will be administered as an Intravenous (IV) infusion at a dose of 16 milligram per kilogram (mg/kg) weekly for the first 3 cycles, on Day 1 of Cycles 4-8 (every 3 weeks), and then on Day 1 of subsequent cycles (every 4 weeks). First 8 Cycles are 21-day cycles; Cycles 9 and onwards are 28-day cycles. |
| Montelukast | DRUG | Administered intravenously or orally only with the first daratumumab dose in accordance with product labeling and local standards. |
| Part 1 (Dose Escalation): Daratumumab | DRUG | Participants will receive intravenous (injection of a substance into a vein) infusion of daratumumab in an increased fashion from 2 milligram per kilogram (mg/kg) up to maximum dose of 16 mg/kg. Considering the safety and efficacy of dose in Part 1, recommended phase 2 dose (RP2D) for Part 2 of the study will be decided. A predose infusion of 10 percent (%) of the full dose of daratumumab will be administered a day before the first full infusion of the first cycle. Participants will receive 4 weekly infusions in the first 2 treatment cycles. From cycles 3 to 6 infusions will be administered every alternate week and monthly infusions will be administered from cycle 7 until disease progression. |
| Part 2 (Dose Expansion): Daratumumab | DRUG | Participants will receive RP2D as determined in Part 1 of the study. Participants will receive 4 weekly infusions of RP2D in the first 2 treatment cycles. From cycles 3 to 6 infusions will be administered every alternate week and monthly infusions will be administered from cycle 7 until disease progression. |
| Darzalex Faspro (Daratumumab and hyaluronidase-fihj) | DRUG | Darzalex Faspro will be administered weekly as a subcutaneous injection on Days -42, -35, -28 and -21 (+/- 1 day) for a total of four doses at 1800 mg each. |
| JH-DSA Semi-Quant Screen and Response Score | DEVICE | Serum based semi-quantifiable investigational testing regimen used to screen for high DSA level or assess response to desensitization. It is based on results from cross-matched flow cytometric assessment cellular-based and solid phase immunoassays (SPI) that estimates antibody level. |
Inclusion Criteria: 1. Documented diagnosis of MM as per IMWG diagnostic criteria. 2. Newly diagnosed patients who have completed a single or tandem autologous stem cell transplant after receiving quadruplet induction (containing an anti-CD38 antibody, an immunomodulatory drug, and a proteasome inh...
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Daratumumab is a monoclonal antibody developed by Johnson & Johnson (ticker JNJ) that targets CD38. It is being studied in Phase 2 clinical trials across several conditions, including amyloidosis, non-small-cell lung carcinoma, cardiac transplant, high-risk smoldering multiple myeloma, kidney failure, and lymphoma. It is also known by the brand name Darzalex and as daratumumab and hyaluronidase-fihj.
Daratumumab targets CD38, a protein found on the surface of certain cells. By binding to CD38, daratumumab acts as an inhibitor of CD38-mediated signaling. This mechanism is being investigated in conditions such as amyloidosis, multiple myeloma, and other plasma cell disorders.
Daratumumab is developed by Johnson & Johnson, which trades under the ticker symbol JNJ. The company is responsible for the clinical development and manufacturing of daratumumab and its subcutaneous formulation, daratumumab and hyaluronidase-fihj.
Daratumumab is in Phase 2 clinical development. It is an investigational agent and has not been approved by the FDA for the indications currently being studied. The Phase 2 program includes trials in amyloidosis, non-small-cell lung carcinoma, cardiac transplant, high-risk smoldering multiple myeloma, kidney failure, and lymphoma.
Daratumumab is being evaluated in several clinical trials, including NCT07649525, a Phase 3 study in multiple myeloma and plasma cell leukemia; NCT07110662, a Phase 1 trial in toxic epidermal necrolysis; NCT07075510, a Phase 1 study of subcutaneous administration in plasma cell disorders; and NCT06889948, a Phase 2 trial in monoclonal gammopathy of renal significance.
Yes, daratumumab is marketed under the brand name Darzalex. It is also known as daratumumab and hyaluronidase-fihj, daratumumab SC, daratumumab IV, and daratumumab injection. These names refer to the same active substance, with some variations indicating the route of administration or combination with hyaluronidase.