Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication Kyprolis is a proteasome inhibitor that is indicated: for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone; or Isatuximab and dexamethasone. FDA label
Carfilzomib · 47 trials · 55 indications
ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-hours). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hours urinary M-protein by ≥ 90% or to \< 200 mg/24-hours. The ORR 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.
Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC). The duration of PFS was right censored for participants who met any of the following conditions: 1. no baseline/post-baseline disease assessments; 2. started a new anti myeloma therapy before documentation of progressive disease or death; 3. progressive disease or death immediately after more than 70 days without disease assessment visit or; 4. alive without documentation of disease progression before the analysis trigger date (PA DCO); 5. lost to follow-up or withdrawn consent.
ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline.
Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.
Progression-free survival was defined as the time from randomization to the earlier of documented disease progression or death due to any cause. PFS was analyzed using Kaplan-Meier methods. The duration of PFS was censored for participants with no baseline and/or post-baseline disease assessments, who started a new anti-cancer therapy before documentation of disease progression or death, death or disease progression after missed disease assessment of 100 consecutive days or longer, or who were alive without documentation of disease progression before the data cutoff date, including lost to follow-up prior to disease progression. Participants were evaluated for disease response and progression according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC), determined centrally using a validated computer algorithm in a blinded manner.
Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC). Median PFS was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
Time elapsed between the randomization date and the date of death. Participants who were still alive were censored at date when the subject is last known alive or the data cutoff date, whichever occurs earlier.
No prior CAR T-cell therapy cohort: Rate of very good partial response (VGPR) or better after 6 cycles according to the 2016 International Myeloma Working Group (IMWG) Response Criteria by Independent Review Committee (IRC).
Prior CAR T-cell therapy cohort: Rate of overall response (ORR) as determined by investigator assessment.
Primary endpoint is the rate of CR or VGPR 12 months after the start of treatment using the response criteria updated at the Sixth IWWM (CR/VGPR).
Simon's two-stage design will be used. An objective response rate of 40%
MRD will be assessed by the MRD scale ranging from 10 (increased disease detection) to -5 (less to no disease detection) after 8 cycles of therapy.
The primary endpoint is a binary variable determined for each subject indicating whether the subject achieved a complete response (CR) or stringent complete response (sCR) to induction treatment with KRd-Dara, as defined by the IMWG 2016 response criteria. Per IMWG 2016 criteria, CR is defined as negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow aspirates. sCR is defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry.
Completed response (CR) rates will be determined for CPd maintenance.
Response rate to protocol treatment after 4 cycles is define by stringent complete response, complete response, partial response, very good partial response, minimal response. Complete response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow biopsy Stringent complete response: Complete response plus Absence of clonal cells in bone marrow d by immunohistochemistry or immunofluorescence Very good partial response: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein with urine M-protein level \<100 mg/24 hours. Partial response: ≥50% reduction in serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours Minimal response: 25-49% reduction in serum M-protein, and 50-89% reduction in 24-hour urinary M-protein, if ≥ 200 mg/24 hours at baseline
Percentage of participants with confirmed complete response (CR) or partial response (PR) (i.e. 2 CRs or PRs at least 4 weeks apart) to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR=disappearance of all target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Overall response was defined as the best overall confirmed response of: Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to \< 200 mg/24-h. Assessment was by IRC per International Myeloma Working Group Uniform Response Criteria (IMWG-URC). The 90% confidence intervals were estimated using the Clopper-Pearson method (1994).
Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required.
Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycle 8. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay. The Premarket Notification 510(k) (Number K130373) for the device can be found using the following link. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K130373.
Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required. Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 4,8,12,18 and 24. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay.
Overall response rate (ORR) will be assessed according to International Myeloma Working Group (IMWG) criteria to determine the ORR in patients NDMM after receiving 9 cycles induction therapy with either carfilzomib in combination with thalidomide and dexamethasone or carfilzomib in combination with lenalidomide and dexamethasone
The safety and efficacy of high dose carfilzomib who developed disease progression on the standard dosing and schedule of carfilzomib as measured by number of participants with adverse events
Participants with peripheral neuropathy or peripheral neuropathy-related adverse events, including hypoaesthesia, paraesthesia, dysaesthesia, and neuropathic pain.
Adverse events (AEs) were assigned a severity grade using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale version 3.0. Per protocol, adverse events were collected if they led to dose modification or dose discontinuation, were grade ≥ 3 or serious, or were events of peripheral neuropathy (any grade). A serious AE is one that met one or more of the following criteria: * Death * Life threatening * Required inpatient hospitalization or prolongation of an existing hospitalization * Resulted in persistent or significant disability/incapacity * A congenital anomaly/birth defect in the offspring of an exposed subject * Important medical events that, based upon appropriate medical judgment, jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes above.
Plasma concentrations of carfilzomib was determined by a validated liquid chromatography tandem mass spectrometry (LC MS/MS) method. The lower limit of quantitation (LLOQ) was 0.300 ng/mL. Concentration values that were below the LLOQ (BLQ) were set to zero. Pharmacokinetic (PK) parameters were calculated from the individual plasma concentrations of carfilzomib using a noncompartmental method.
ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level \< 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to \< 200 mg per 24 hours.
For both A0 and A1, to evaluate the best overall response rate (stringent complete response \[sCR\]+ complete response \[CR\]+ very good partial response \[VGPR\]+ partial response \[PR\]) in patients with multiple myeloma who had previously received bortezomib and either thalidomide or lenalidomide, had relapsed after two or more therapies, and were refractory to the most recently received therapy
The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.0) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.
Overall response rate (CR and PR) after 3 cycles of C R ICE in patients age of 18 to 75 with relapsed/refractory CD20-positive DLBCL treated with rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, R-HyperCVAD, etc.) induction. Response was based on a Modified Cheson Criteria with Complete response (CR): All lesions with a longest diameter ≤ 15 mm or short axis ≤ 10 mm (Not palpable during the clinical examination, No visible nodule on imaging, And disappearance of all non-nodal target lesions Or in case of hypermetabolic disease on the baseline PET scan, negative PET scan whatever the appearance of lesions on CT) and Partial Response (PR): ≥ 50 % of sum of the products of the diameters (SPD) of target lesions or in the case of hypermetabolic lesions on the baseline PET scan, persistence of at least one PET-positive site without progression of other lesions on CT (≥ 50 % of SPD of target lesions (or longest diameter if a single nodule) No clinically enlarged liver or spleen)
Review of adverse events for safety and to determine the maximum tolerated dose of the combination treatment
The maximum tolerated dose of carfilzomib that can be safely combined with high dose melphalan as conditioning regimen prior to autologous hematopoietic cell transplantation in patients with relapsed multiple myeloma meeting eligibility criteria.
VGPR defined as any one of the following: ≥ 90% reduction of serum M-protein; ≥ 90% reduction in 24-hour urinary M-protein or decrease to \< 100 mg per 24 hour; ≥ 50% decrease in the difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio; ≥ 50% reduction in bone marrow plasma cells; ≥ 50% reduction in the size of soft tissue plasmacytomas.
CR defined as the following: Negative immunofixation of the serum and urine. If only the measurable non-bone marrow parameter was free light chain, normalization of free light chain ratio. \< 5% plasma cells in bone marrow. And, disappearance of any soft tissue plasmacytomas.
Neutrophil engraftment is defined as the first of three consecutive days with absolute neutrophil count \>500/mm3. Platelet engraftment is defined as the first of 3 consecutive days of platelets \> 20,000/mm3 without platelet transfusion in the prior 7 days.
Grading of AE's is performed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
MTD of carfilzomib, determined by incidence of dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
DLTs will be determined for each subject enrolled in Phase I as a binary variable indicating whether the subject experienced a DLT during Cycle 1 of belantamab mafodotin-containing protocol directed induction therapy.
CR will be determined for each subject as a binary variable indicating whether the achieved a best overall response to induction therapy of CR or better.
MTD as determined by the continual reassessment model (CRM) with a predefined target Dose Limiting Toxicity (DLT) probability of 25%
Assessed using the International response criteria
Safety and tolerability were evaluated according to the type, incidence, and severity of adverse events. An AE is defined as any untoward medical occurrence in a clinical trial subject. The event does not necessarily have a causal relationship with study treatment. A serious adverse event is defined as an AE that meets at least 1 of the following serious criteria: * fatal * life threatening * requires in-patient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * congenital anomaly/birth defect * other medically important serious event The severity of each AE was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.
An adverse event (AE) is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. Treatment-related AEs (TRAEs) were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
A DLT was defined as any of the following toxicities assessed by the investigator as possibly, probably, or definitely attributable to carfilzomib, with protocol defined exclusions: Any Grade 4 nonhematologic toxicity, ≥ Grade 4 neutropenia or ≥ Grade 3 thrombocytopenia.
CR was defined as: 1. Attainment of M1 bone marrow status (less than 5% blasts in a bone marrow aspirate and at least 200 cells counted) with no evidence of circulating blasts or extramedullary disease. 2. Recovery of peripheral counts: * Absolute neutrophil count (ANC) greater than or equal to 1000/µL * Platelet count greater than or equal to 100000/µL. * Assessed between days 29 and 45 Data was adjusted as inverse probability of treatment weight (IPTW) for the average treatment effect of the treated (IPTW-ATTW).
Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D
Carfilzomib plasma concentrations for pharmacokinetic (PK) analyses were measured by liquid chromatography with tandem mass spectrometry. The lower limit of quantitation (LLOQ) for the assay was 0.3 ng/mL.
The maximum tolerated dose (MTD) was defined as the highest dose level at which \< 33% of participants experienced a dose-limiting toxicity (DLT) during the first 21-day cycle. Dose-limiting toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. A DLT was defined as: * A grade 3 or greater non-hematologic toxicity that was assessed as related to carfilzomib by the investigator except in the case of neuropathy. A grade 2 or higher neuropathy with pain was considered a DLT. * Grade 4 neutropenia: absolute neutrophil count (ANC) \< 500 mm³, lasting ≥ 7 days despite granulocyte colony stimulating factor support, or any febrile (temperature \> 38.3°C) neutropenia (ANC \< 1000 mm³). * Thrombocytopenia of any grade associated with clinically significant bleeding or platelet/blood transfusion * Grade 4 fatigue lasting ≥ 7 days * Grade 3 nausea, vomiting or diarrhea lasting ≥ 7 days.
The area under the curve from time zero (defined as the start of carfilzomib infusion) to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
The MTD is defined as the highest carfilzomib dose at which fewer than 33% of participants experience a treatment-related dose-limiting toxicity (DLT) during the first 28-day cycle. The number of participants who experienced a DLT is reported. Dose-limiting toxicities are defined as any of the following carfilzomib-related adverse events: Nonhematologic: * ≥ Grade 3 non-hematological toxicity * ≥ Grade 3 acute kidney injury (creatinine \> 3 × baseline or \> 4.0 mg/dL) lasting \> 72 hours Hematologic: * Grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 0.5 × 10\^9/L) lasting for \> 7 days * Febrile neutropenia (ANC \< 1.0 × 10\^9/L with a fever ≥ 38.3ºC) of any duration * Grade 4 thrombocytopenia (\< 25 × 10\^9/L) that persists for \> 14 days, despite holding treatment * Grade 3 or 4 thrombocytopenia associated with \> Grade 1 bleeding
The MTD was defined as the highest carfilzomib dose at which \< 33% of participants had a treatment-related DLT during the first 28-day cycle. A DLT was categorized as nonhematologic or hematologic and defined as follows: Nonhematologic: * ≥ grade 3 nonhematological toxicity (excluding nausea, vomiting, diarrhea, fatigue lasting \< 14 days, increased serum creatinine or electrolyte abnormalities not clinically significant or requiring treatment) * ≥ grade 3 acute kidney injury (creatinine \> 3 x baseline or \> 4.0 mg/dL) lasting \> 72 hours * ≥ grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy Hematologic: * grade 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/mm³) for \> 7 days * febrile neutropenia (ANC \< 1000/mm³ with a fever ≥ 38.3ºC) of any duration * grade 4 thrombocytopenia (\< 25 000/mm³) for \> 14 days, despite holding treatment * grade 3 or 4 thrombocytopenia (\< lower limit of normal) associated with \> grade 1 bleeding
Participants were evaluated for dose-limiting toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 3.0. A DLT was defined as treatment-related ≥ Grade 2 neuropathy with pain, ≥ Grade 3 non-hematologic toxicity, Grade 4 neutropenia or thrombocytopenia lasting 7 or more days, or thrombocytopenia with bleeding. The maximum tolerated dose (MTD) for each of the 3 populations (solid tumor, multiple myeloma, and lymphoma) was defined as the dose level at which \< 33% of participants experienced a dose-limiting toxicity during the first 28-day cycle.
Overall response is defined as participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) after 4 cycles, assessed by the Investigator using tumor measurement and according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target and non-target lesions and no new lesions; PR: Disappearance of all target lesions, persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits and no lesions, or, at least a 30% decrease in the size of target lesions and no progression of existing non-target lesions or any new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest size since the treatment started, and no progression of existing non-target lesions or any new lesions.
| Arm | Type | Description |
|---|---|---|
| Carfilzomib once-weekly | ACTIVE_COMPARATOR | Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2 |
| Carfilzomib twice-weekly | ACTIVE_COMPARATOR | Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2 |
| Kd - Carfilzomib and Dexamethasone | ACTIVE_COMPARATOR | Carfilzomib was administered intravenously (IV) at 20 mg/m\^2 in Cycle 1: days 1 and 2; at 56 mg/m\^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m\^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16. Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles. |
| KdD - Carfilzomib, Dexamethasone and Daratumumab | EXPERIMENTAL | Carfilzomib was administered intravenously (IV) at 20 mg/m\^2 in Cycle 1: days 1 and 2; at 56 mg/m\^2 in Cycle 1: days 8, 9, 15 and 16. The 56 mg/m\^2 dosage was continued in Cycles 2+ on days 1, 2, 8, 9, 15 and 16. Dexamethasone was taken by IV infusion at 20 mg on Cycle 1, days 1 and 2 (in Cycles 2+, days 1 and 2 could be either oral or IV) and either orally or by IV infusion on days 8, 9, 15 and 16 and at 40 mg on day 22 of all 28-day cycles. The administration of dexamethasone was given on carfilzomib and/or daratumumab IV infusion days. Daratumumab was administered by IV at 8 mg/kg on Cycle 1: days 1 and 2; at 16 mg/kg on Cycle 1: days 8, 15 and 22, and Cycle 2: days 1, 8, 15, and 22. The 16 mg/kg dosage was continued on Cycles 3-6: days 1 and 15. The 16 mg/kg was further continued on Cycles 7+: day 1 only. |
| Carfilzomib with Dexamethasone | EXPERIMENTAL | Participants will receive carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants will also receive 20 mg dexamethasone IV or orally on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. Participants will receive treatment until disease progression, unacceptable toxicity, initiation of new antimyeloma therapy, withdrawal of consent, non-compliance, or intercurrent illness or worsening of a chronic condition, whichever occurs first. |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | EXPERIMENTAL | Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | EXPERIMENTAL | Participants received carfilzomib administered by IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. |
| Carfilzomib, Melphalan, Prednisone | EXPERIMENTAL | Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m². |
| Bortezomib, Melphalan, Prednisone | ACTIVE_COMPARATOR | Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m². |
| Carfilzomib plus Dexamethasone | EXPERIMENTAL | Participants received 20 mg/m² carfilzomib administered by intravenous (IV) infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle. |
| Bortezomib plus Dexamethasone | ACTIVE_COMPARATOR | Participants received bortezomib 1.3 mg/m² administered IV or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle. |
| Best Supportive Care | ACTIVE_COMPARATOR | - |
| Carfilzomib | EXPERIMENTAL | - |
| Lenalidomide and Dexamethasone (Rd) | ACTIVE_COMPARATOR | Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22. |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | EXPERIMENTAL | Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher. |
| Cohort 1: No Prior CAR T-Cell Therapy | EXPERIMENTAL | This cohort will consist of 19 participants who have not had CAR T-Cell Therapy. Participants will receive belantamab mafodotin, carfilzomib, pomalidomide and dexamethasone. |
| Cohort 2: Prior CAR T-Cell Therapy | EXPERIMENTAL | This cohort will consist of 64 participants who have had prior CAR T-Cell Therapy. Participants will receive belantamab mafodotin, carfilzomib, pomalidomide and dexamethasone. |
| Arm A: Carfilzomib + Ibrutinib | EXPERIMENTAL | Patients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated. Patients will receive in addition Carfilzomib for two years. |
| Arm B: Ibrutinib | ACTIVE_COMPARATOR | Patients will be treated with Ibrutinib until evidence of progressive disease or no longer tolerated. |
| Daratumumab,Carfilzomib, Pomalidomide and Dexamethasone | EXPERIMENTAL | Patients who meet eligibility criteria for the study will subsequently be enrolled for treatment. Participants will receive daratumumab, carfilzomib, pomalidomide, and dexamethasone on a 28 day schedule. * Daratumumab will be given according to cycle and dosage determined by protocol. * Carfilzomib will be given at 56 mg/m2 on days 1, 8, 15 (except for C1D1 where it is 20 mg/m2) * Pomalidomide will be given daily on days 1-21. * Dexamethasone will be given weekly, split over two days. |
| Arm A - Bortezomib, Lenalidomide and Dexamethasone (VRD) | EXPERIMENTAL | Participants in this group will receive Bortezomib, Lenalidomide and Dexamethasone on a 21 day treatment cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years. |
| Arm B - Carfilzomib, Lenalidomide and Dexamethasone (KRD) | EXPERIMENTAL | Participants in this group will receive Carfilzomib, Lenalidomide and Dexamethasone on a 28 day cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years. |
| Arm C- Carfilzomib, Lenalidomide and Dexamethasone with Daratumumab (DKrd) | EXPERIMENTAL | Participants in this group will receive Carfilzomib, Lenalidomide, Dexamethasone with Daratumumab, Acetaminophen, Diphenhydramine and Montelukast on a 28 day cycle. Participants achieving a PR or better at the end of 4 cycles will continue to receive a total of 8 cycles of combination therapy. Participants with less than PR after completing 4 cycles will go off study therapy. After 8 cycles of therapy, participants who are MRD positive will have the option to receive an ASCT if stem cells were able to be extracted, before initiating maintenance therapy with Lenalidomide for up to 2 years, and patients who are MRD negative will go directly on to receive maintenance therapy with Lenalidomide for up to 2 years. |
| KRd-Daratumumab | EXPERIMENTAL | Induction: Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab |
| Treatment Arm (D-KRd) | EXPERIMENTAL | - |
| Carfilzomib, pomalidomide, dexamethasone | EXPERIMENTAL | Patients receive carfilzomib IV over 30 minutes on days 1, 8, and 15, pomalidomide PO daily on days 1-21, and dexamethasone PO daily on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Carfilzomib plus cyclophosphamide plus dexamethasone | EXPERIMENTAL | 20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (\< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg |
| Carfilzomib combined with pomalidomide and dexamethasone | EXPERIMENTAL | Carfilzomib, pomalidomide, and dexamethasone (KPd) |
| Elo-KRd regimen | EXPERIMENTAL | Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. A treatment decision was made after cycle 12 based on these results. There are three outcomes based on the IFM trial (Avet-Loiseau et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 12, the subject went on E-Rd maintenance until disease progression. 2) If the subject is MRD-positive after cycle 8 but MRD-negative after cycle 12, 6 more cycles of E-KRd was given and at the end of 18 cycles, the subject went on E-Rd maintenance until disease progression. 3) Finally, if the subject is MRD-positive at both instances, 12 additional cycles of E-KRd was given and at the end of 24 cycles total, the subject went on E-Rd maintenance until disease progression. |
| Induction Arm A | EXPERIMENTAL | Carfilzomib + Thalidomide + Dexamethasone (KTd) for 9 cycles (day 1-28) Followed by second randomisation: maintenance arm with carfilzomib monotherapy versus "observation only" arm |
| Induction Arm B | ACTIVE_COMPARATOR | Carfilzomib + Lenalidomide + Dexamethasone (KRd) for 9 cycles (day 1-28) Followed by second randomisation: maintenance arm with carfilzomib monotherapy versus "observation only" arm |
| carfilzomib (A0) | EXPERIMENTAL | - |
| carfilzomib (A1) | EXPERIMENTAL | - |
| Treatment (carfilzomib and hyper-CVAD) | EXPERIMENTAL | Patients receive carfilzomib IV over 30 minutes on days 0, 1, 7, and 8. Patients also receive hyper-CVAD comprising cyclophosphamide IV over 2 hours every 12 hours for 6 doses beginning on day 1, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV over 2-24 hours on day 4, and dexamethasone PO on days 1-4 and 11-14 (courses 1 and 3) and methotrexate IV over 24 hours on day 1, cytarabine IV over 2 hours every 12 hours for 4 doses starting on day 2, leucovorin calcium IV or PO every 6 hours beginning 36 hours after the start of methotrexate infusion, and methylprednisolone IV every 12 hours for 6 doses beginning on day 1 (courses 2 and 4). Patients with CD20 positive disease also receive rituximab twice daily on days 1 and 11 of courses 1 and 3 and days 1 and 8 of courses 2 and 4. Treatment repeats every 3-4 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. |
| Treatment (carfilzomib, rituximab, chemotherapy) | EXPERIMENTAL | Patients receive carfilzomib IV over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. |
| Carfilzomib, Cyclophosphamide, Dexamethasone | EXPERIMENTAL | All eligible subjects will receive Carfilzomib, Cyclophosphamide, and Dexamethasone. |
| Carfilzomib + high dose melphalan | EXPERIMENTAL | Single arm. |
| Combo of Panobinostat and Carfilzomib | EXPERIMENTAL | A cycle of therapy is 4 weeks (28 days in duration). Carfilzomib (with dexamethasone during cycle 1) will be administered intravenously infusion on days 1, 2 and 8, 9 and 15, 16 of every 28 day cycle. Panobinostat is administered orally three times per week. |
| Treatment (carfilzomib) | EXPERIMENTAL | Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. |
| Phase I | EXPERIMENTAL | Carfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin |
| Phase II | EXPERIMENTAL | Carfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin |
| Dose Level 1 | EXPERIMENTAL | 8mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/36mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. |
| Dose Level 2 (starting dose) | EXPERIMENTAL | 10mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/36mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. |
| Dose Level 3 | EXPERIMENTAL | 10mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/45mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. |
| Dose Level 4 | EXPERIMENTAL | 12mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/45mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. |
| Dose Level 5 | EXPERIMENTAL | 12mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/56mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. |
| Dose Level 6 | EXPERIMENTAL | 14mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/56mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. |
| RRMM Dose-evaluation: Carfilzomib 56 mg/m² | EXPERIMENTAL | Participants with relapsed or refractory multiple myeloma (RRMM) received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 56 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. |
| RRMM Dose-evaluation: Carfilzomib 70 mg/m² | EXPERIMENTAL | Participants with RRMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. |
| RRMM Dose-expansion: Carfilzomib 70 mg/m² | EXPERIMENTAL | Participants with RRMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. |
| NDMM Dose-evaluation: Carfilzomib 56/70 mg/m² | EXPERIMENTAL | Participants with newly diagnosed multiple myeloma (NDMM) received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1 day 1, 56 mg/m² on cycle 1 days 8 and 15, and then 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. |
| NDMM Dose-expansion: Carfilzomib 70 mg/m² | EXPERIMENTAL | Participants with NDMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 70 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. |
| NDMM Dose-expansion: Carfilzomib 56 mg/m² | EXPERIMENTAL | Participants with NDMM received treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) for up to eighteen 28-day cycles, or until disease progression, patient withdrawal, stem cell transplant, or death. Participants received carfilzomib on days 1, 8, and 15 of each cycle. The dose was 20 mg/m² on cycle 1, day 1, and 56 mg/m² thereafter. Participants also received lenalidomide 25 mg once daily on days 1-21 and dexamethasone 40 mg (oral or IV) on days 1, 8, and 15 of each cycle, and on day 22 of cycles 1 to 8. |
| Phase 1b: Dose Escalation 1 | EXPERIMENTAL | Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. |
| Phase 1b: Dose Escalation 2 | EXPERIMENTAL | Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. |
| Phase 2: Aged ≥ 12 months at screening | EXPERIMENTAL | All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. |
| Phase 2: Aged < 12 months at screening | EXPERIMENTAL | All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. |
| Normal Renal Function | EXPERIMENTAL | Participants with normal renal function (creatinine clearance \[CrCl\] ≥ 75 mL/min) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death. |
| End Stage Renal Disease | EXPERIMENTAL | Participants with end-stage renal disease (on hemodialysis) received carfilzomib 20 mg/m² intravenous infusion (IV) on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. Participants continued treatment until confirmed progressive disease, unacceptable toxicity, withdrawal of consent, study closure, or death. |
| Carfilzomib Combination | EXPERIMENTAL | Participants received carfilzomib on days 2, 3, 9, and 10 of each 21-day cycle as per the dose escalation schema, carboplatin at a target area under the curve (AUC) of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest. |
| Normal Hepatic Function | EXPERIMENTAL | Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. |
| Mild Hepatic Impairment | EXPERIMENTAL | Participants with mild hepatic impairment (bilirubin \> 1-1.5 x ULN or AST \> ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. |
| Moderate Hepatic Impairment | EXPERIMENTAL | Participants with moderate hepatic impairment (bilirubin \> 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. |
| Severe Hepatic Impairment | EXPERIMENTAL | (Bilirubin \> 3 × ULN; any AST) Participants with severe hepatic impairment (bilirubin \> 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. |
| Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) | EXPERIMENTAL | Participants received carfilzomib, cyclophosphamide and dexamethasone for up to eight 28-day cycles, or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. |
| Carfilzomib + Lenalidomide + Dexamethasone | EXPERIMENTAL | Treatment during Cycles 1 through 12 consisted of carfilzomib (15, 20, or 20/27 mg/m²) on Days 1, 2, 8, 9, 15, and 16; lenalidomide (10, 15, 20, or 25 mg) on Days 1 to 21; and low-dose dexamethasone (40 mg) given 30 minutes to 4 hours before the carfilzomib dose on Days 1, 8, and 15, as well as on Day 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion. |
| Phase 1B Solid Tumors: Carfilzomib 20 mg/m² Bolus | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 20/27 mg/m² Bolus | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 27 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 20/36 mg/m² Bolus | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 2 Solid Tumors: Carfilzomib 20/36 mg/m² Bolus | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by bolus intravenous infusion over 2-10 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 36 mg/m² | EXPERIMENTAL | Participants received carfilzomib 36 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 45 mg/m² | EXPERIMENTAL | Participants received carfilzomib 45 mg/m² administered by intravenous infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for at least 2 cycles. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 20/45 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 20/56 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1B Solid Tumors: Carfilzomib 20/70 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b Multiple Myeloma: Carfilzomib 20/36 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 36 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b Multiple Myeloma: Carfilzomib 20/45 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b Multiple Myeloma: Carfilzomib 20/56 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b Multiple Myeloma: Carfilzomib 20/70 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b Lymphoma: Carfilzomib 20/56 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b Lymphoma: Carfilzomib 20/70 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 70 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b MM: Carfilzomib 20/45 mg/m² + Dexamethasone | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 45 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| Phase 1b MM: Carfilzomib 20/56 mg/m² + Dexamethasone | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous infusion over 30 minutes on Cycle 1 Days 1 and 2 only, then 56 mg/m² on Days 8, 9, 15 and 16 and thereafter for the remainder of treatment plus dexamethasone 40 mg weekly. All participants with stable disease or better after 2 cycles could continue treatment until progressive disease or unacceptable toxicity. |
| CFZ 1.2 mg/m² | EXPERIMENTAL | Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 2.4 mg/m² | EXPERIMENTAL | Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 4.0 mg/m² | EXPERIMENTAL | Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 6.0 mg/m² | EXPERIMENTAL | Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 8.4 mg/m² | EXPERIMENTAL | Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 11.0 mg/m² | EXPERIMENTAL | Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 15.0 mg/m² | EXPERIMENTAL | Participants received carfilzomib 115.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 20.0 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 27.0 mg/m² | EXPERIMENTAL | Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. |
| CFZ 20/27 mg/m² | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. |
| CFZ 20/27 mg/m² + DEX | EXPERIMENTAL | Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly). |
| Name | Type | Description |
|---|---|---|
| Carfilzomib | DRUG | Once weekly IV over 30 minutes on day 1, 8 and 15 of each 28 day cycle. The dose will be 20 mg/m2 on cycle 1 day 1 and 56 mg/m2 beginning with cycle 1 day 8 and thereafter. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent. |
| Lenalidomide | DRUG | Once daily orally 25 mg days 1 to 21 of each cycle. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent |
| Dexamethasone | DRUG | Once daily orally or by IV 40 mg days 1, 8 and 15 of each cycle. Also day 22 of cycles 1 to 9. 12 cycles or until progression, unacceptable toxicity, death, loss to follow up or withdrawal of consent |
| Daratumumab | DRUG | Daratumumab was supplied as a concentrated solution for infusion in single-use vials. |
| Bortezomib | DRUG | Bortezomib 1.3 mg/m² was administered as a bolus IV injection or as a subcutaneous injection (per investigator's choice, dose modification, or regulatory approval) on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycles 1 to 4, and on days 1, 8, 22, and 29 of cycles 5 to 9. |
| Melphalan | DRUG | Melphalan 9 mg/m² was taken orally on days 1 to 4 of all cycles. |
| Prednisone | DRUG | Prednisone 60 mg/m² was taken orally on days 1 to 4 of all cycles. |
| Best Supportive Care | DRUG | Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle). |
| Belantamab mafodotin | DRUG | Cycles 1, 3, 5, 7, etc. (odd numbered cycles): 1.9 mg/kg IV on Day 1 (28-day cycles) |
| Pomalidomide | DRUG | 3 mg Day 1-21 of 28-day Cycle |
| Carfilzomib + Ibrutinib | DRUG | Carfilzomib: Cycle 1, day 1: 20 mg/m² i.v. Cycle 1, day 8, day 15: 70 mg/m² i.v. Cycle 2 - 12, day 1, day 8, day 15: 70 mg/m² i.v. Cycle 13 - 24, day 1, day 15: 70 mg/m² i.v. Ibrutinib: 420 mg p.o daily until disease progression or non-tolerable toxicities |
| Ibrutinib | DRUG | Ibrutinib: 420 mg p.o daily until disease progression or non-tolerable toxicities |
| Acetaminophen | DRUG | 650 mg administered PO. Participants randomized to Arm C: Cycles 1 through 8 - 650 mg administered on Days 1, 8 and 15. |
| Diphenhydramine | DRUG | 25 mg administered via IV Participants randomized to Arm C: Cycles 1 through 8 - 25 mg administered on Days 1, 8 and 15. |
| Montelukast | DRUG | 10 mg administered PO to participants randomized to Arm C prior to the first 4 doses of Daratumumab. |
| Autologous Stem Cell Transplant (ASCT) | BIOLOGICAL | Participants who are MRD positive at the conclusion of 8 cycles of study treatment, and were able to have their stem cells that were extracted, will receive ASCT from participants' bone marrow samples. |
| Carfilzomib, lenalidomide, dexamethasone (KRd) + Daratumumab | DRUG | Experimental |
| Cyclophosphamide | DRUG | - |
| Elotuzumab | DRUG | Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15 |
| Thalidomide | DRUG | 100mg orally on days 1-28 in patients \<75 years of age at Cycle 1; 50mg p.o. on days 1-28 in patients ≥ 75 years of age at Cycle 1 |
| Acyclovir | DRUG | Administered orally twice daily |
| vincristine sulfate | DRUG | Given IV |
| doxorubicin hydrochloride | DRUG | Given IV |
| methotrexate | DRUG | Given IV |
| cytarabine | DRUG | Given IV |
| leucovorin calcium | DRUG | Given IV or PO |
| methylprednisolone | DRUG | Given IV |
| rituximab | BIOLOGICAL | - |
| laboratory biomarker analysis | OTHER | Correlative studies |
| Carboplatin | DRUG | Given IV |
| Etoposide | DRUG | Given IV |
| Ifosfamide | DRUG | Given IV |
| Pharmacological Study | OTHER | Correlative studies |
| Panobinostat | DRUG | Panobinostat will be supplied as 5-mg or 20-mg pink/opaque-colored, hard gelatin capsules. Panobinostat is administered orally three times per week. * Standard 3+3 design * 3 out of 4 weeks |
| Carfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin | DRUG | Phase I - Chemotherapy multiple agents systemic Phase II - Maximum Tolerated Dose from Phase I |
| Romidepsin | DRUG | 10mg vial for Injection |
| Mitoxantrone | DRUG | - |
| PEG-asparaginase | DRUG | - |
| Vincristine | DRUG | - |
| Intrathecal (IT) Methotrexate | DRUG | - |
| Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) | DRUG | - |
| 6-Mercaptopurine | DRUG | - |
| Daunorubicin | DRUG | - |
Inclusion Criteria: Multiple myeloma with documented relapse or progression after most recent myeloma treatment. Subjects refractory to the most recent line of therapy are eligible, unless last treatment contained proteasome inhibitor (PI) or lenalidomide and dexamethasone. Refractory is defined as...
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Carfilzomib is a small molecule oncology drug developed by Amgen Inc. (ticker AMGN). It is being studied across several blood cancers and solid tumors, including acute lymphoblastic leukemia, adult nasal type extranodal NK/T-cell lymphoma, amyloidosis, CD20 positive disease, contiguous stage II adult lymphoblastic lymphoma, and extensive-stage small-cell lung cancer.
Carfilzomib targets the proteasome subunits PSMD1, PSMB2, PSMB1, PSMB5, PSMB8, and PSMB9, acting as an inhibitor. By binding these proteasome components, it interferes with protein degradation in cells, which is the basis for its study in oncology indications.
Carfilzomib is developed by Amgen Inc., which trades under the ticker AMGN. Amgen is the sponsor behind the clinical development program covering the drug's oncology indications and its combination studies.
Carfilzomib is in Phase 1 development and remains investigational. Its clinical program includes 22 trials in total, with 5 currently active and 17 completed, spanning multiple oncology indications and combination regimens.
Carfilzomib trials include NCT05789303, a Phase 2 study with belantamab mafodotin, pomalidomide, and dexamethasone in relapsed multiple myeloma, and NCT04822337, a Phase 1 study with lenalidomide, dexamethasone, and belantamab mafodotin. Other studies include NCT04268498 in newly diagnosed multiple myeloma and NCT04263480 in Waldenstrom macroglobulinemia.
No. Carfilzomib is a distinct agent, though it is studied in combination regimens that include lenalidomide, dexamethasone, belantamab mafodotin, daratumumab, and ibrutinib. Searches for carfilzomib plus lenalidomide and dexamethasone, or KRd with daratumumab, refer to those combination therapies rather than to carfilzomib alone.