Multiple Myeloma
Conditions
Brief summary
The purpose of the Phase 1 part of the study is to determine the maximum tolerated dose and assess the safety, tolerability and activity of oprozomib in combination with pomalidomide and dexamethasone in adults with primary refractory or relapsed and refractory multiple myeloma. The purpose of the Phase 3 part of the study is to compare the efficacy for adults with primary refractory or relapsed and refractory multiple myeloma who are randomized to either oprozomib or placebo in combination with pomalidomide and dexamethasone.
Detailed description
This was a phase 1b/3, multicenter study composed of 2 parts: part 1 was a phase 1b, open-label, dose-escalation and dose-expansion component and part 2 was to have been a phase 3, placebo-controlled, double-blind, randomized component. Part 2 was not conducted. The Phase 1 dose-escalation portion of the study followed a standard 3 + 3 dose-escalation design. For each of the 2 schedules, groups of 3 to 6 patients were enrolled. The starting doses of oprozomib were 150 and 210 mg in the 5/14 and 2/7 schedules, respectively. The starting dose of pomalidomide was 4 mg in both schedules. As long as \< 33% of patients experienced a dose-limiting toxicity (DLT) in a given cohort, the dose of oprozomib was escalated in 30-mg increments for successive cohorts. Once the recommended dose and schedule for the expansion phase had been selected, additional participants were enrolled in the dose expansion portion of part 1 to continue the evaluation of the safety and efficacy of the regimen and determine the recommended phase 3 dose. Enrollment was halted during the dose expansion phase and part 2 was not conducted.
Interventions
DRUGOprozomib
Extended release (ER) tablets administered orally
DRUGPomalidomide
Capsules for oral administration
DRUGDexamethasone
Tablets for oral administration
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Multiple myeloma that is primary refractory or relapsed and refractory after at least 2 lines of standard for multiple myeloma including: 1. ≥ 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide (alone or in combination) 2. In the dose-expansion and Phase 3 portions of the study only: In addition to the above, treatment with adequate alkylator therapy, defined as: i. High-dose melphalan or other alkylating agent as conditioning for autologous or allogeneic stem cell transplant (SCT), or ii. ≥ 6 cycles of induction therapy, or iii. Progressive disease after ≥ 2 cycles 2. Disease progression on or within 60 days of completion of the last therapy 3. Measurable disease as indicated by 1 or more of the following: 1. Serum M-protein ≥ 500 mg/dL 2. Urine M-protein ≥ 200 mg/24 h 3. For patients without measurable serum or urine M protein, serum free light chain (SFLC): Involved free light chain (FLC) concentration ≥ 10 mg/dL provided SFLC ratio is abnormal 4. Males and females ≥ 18 years old 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Key
Exclusion criteria
1. Systemic chemotherapy with approved or investigational anticancer therapeutics, intended to treat underlying malignancy, within 3 weeks before the first dose or 6 weeks for antibody therapy 2. Dexamethasone at cumulative doses greater than 160 mg or equivalent within 21 days prior to the first dose of study treatment is not allowed. Use of topical or inhaled steroids is acceptable. 3. Radiation therapy within 3 weeks before first dose. Radioimmunotherapy within 8 weeks before first dose. 4. Plasmapheresis is not permitted at any time during the Screening period or while the subject is receiving study treatment. If a subject has started Screening procedures requiring plasmapheresis, or is anticipated to require plasmapheresis during or after the Screen 5. Autologous SCT within 8 weeks or allogeneic SCT within 16 weeks prior to initiation of study treatment. Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (as defined in Filipovich 2005). 6. Known hypersensitivity to any immunomodulatory drugs (IMiDs), including Grade 4 rash 7. Prior treatment of any duration with pomalidomide 8. Known hypersensitivity or intolerance to dexamethasone 9. Prior exposure to oprozomib 10. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months before first dose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1, 28 days | DLTs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, defined as any of the following treatment-related events occurring within 4 weeks after the first dose of therapy: Any grade ≥ 3 nonhematologic toxicity, except: Grade 3 asymptomatic electrolyte abnormalities or hypophosphatemia for \< 24 hours; Grade 3 nausea, vomiting or diarrhea unless for \> 3 days despite optimal supportive care; Grade 3 fatigue for \< 14 days; Grade ≥ 3 hyperglycemia or toxicity attributed to dexamethasone and Grade ≥ 3 rash attributed to pomalidomide. Hematologic toxicities: * Grade 4 neutropenia: Absolute neutrophil count \< 0.5 × 10\^9/L for ≥ 7 days despite adequate growth factor support; febrile neutropenia * Thrombocytopenia: Grade 4 for ≥ 7 days, or Grade 4 for \< 7 days with grade 2 clinically significant bleeding or \< 10,000 platelets requiring transfusion, or Grade 3 with clinically significant bleeding or requiring platelet transfusion. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From first dose of any study drug up to 30 days after the last dose; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | Adverse events (AEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. A serious AE is an event that met 1 or more of the following criteria: * Death * Life-threatening experience * 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 female subject or offspring of a female partner of a male subject * Important medical events that, based upon appropriate medical judgment, jeopardized the participant and may have required medical or surgical intervention to prevent an outcome listed above. Treatment-related AEs (TRAE) are those considered related to at least 1 study drug by the investigator. |
| Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Cycles 1 and 2 days 1, 5, 15, and 19 and days 3 and 8 of cycle 1, and day 1 of each cycle from cycle 3 thereafter until the end of treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | Laboratory abnormalities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Full chemistry panel included sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total protein, albumin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), phosphorous, and magnesium. Complete blood count (CBC) with differential included hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. |
| Overall Response Rate (ORR) | Disease response was assessed every 4 weeks for the first 18 months and then every 8 weeks for the remainder of study treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | 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. 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 the difference between involved and uninvolved free light chain levels (dFLC). A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. 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 serum FLC (SFLC), ≥ 90% decrease in dFLC. CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow (BM). Normal SFLC ratio if disease measurable only by SFLC. sCR: As for CR, and absence of clonal plasma cells in BM. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The area under the plasma concentration-time curve from time 0 to time infinity (AUCinf), estimated as the sum of AUClast and Clast/λz, where Clast is the last predicted concentration and λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear decay phase. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method. |
| Clinical Benefit Rate (CBR) | Disease response was assessed every 4 weeks for the first 18 months and then every 8 weeks for the remainder of study treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively. | Clinical benefit rate is defined as the percentage of participants with a best overall response of minimal response (MR) per modified European Group for Blood and Marrow Transplantation criteria, or PR, VGPR, CR, or sCR as determined by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). MR: * ≥ 25% but \< 49% reduction in serum M-protein and a 50 - 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg per 24 hours * If the serum and urine M-protein were not measurable, a decrease of 25 - 49% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. * For patients with nonsecretory myeloma only, 25 - 49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed * 25 - 49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination) |
| Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose. | Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 12 centers in the United States. This study was composed of 2 parts: part 1 was a phase 1b, open-label, dose-escalation and dose-expansion component and part 2 was to have been a phase 3, placebo-controlled, double-blind, randomized component. Part 2 was not conducted.
Pre-assignment details
In part 1 participants were enrolled sequentially using a standard 3 + 3 dose escalation schema. Additional participants were to be enrolled in the dose expansion portion once the recommended dose and schedule had been selected; enrollment was halted after 12 participants were enrolled in the expansion cohort.
Participants by arm
| Arm | Count |
|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg/day on days 1 to 21 and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | 3 |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone Participants received oprozomib 150 mg once daily on days 1 to 5 and days 15 to 19 (5/14 schedule) of each 28-day treatment cycle, in combination with pomalidomide 2 mg/day on days 1 to 21 and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | 1 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | 7 |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone Participants received oprozomib 240 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | 10 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase Participants received oprozomib 210 mg once daily on days 1, 2, 8, 9, 15, 16, 22, and 23 (2/7 schedule) of each 28-day treatment cycle, in combination with pomalidomide 4 mg on days 1 through 21 and dexamethasone 20 mg/day on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle until disease progression or unacceptable toxicity. | 10 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Discontinued before receiving treatment | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 9.3 | 54.7 years STANDARD_DEVIATION 5.5 | 63.7 years STANDARD_DEVIATION 6 | 68.2 years STANDARD_DEVIATION 7.3 | 57.1 years STANDARD_DEVIATION 12.9 | 59.0 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 (Fully active) | 9 Participants | 0 Participants | 3 Participants | 4 Participants | 2 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1 (Restricted but ambulatory) | 19 Participants | 3 Participants | 6 Participants | 4 Participants | 5 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2 (Ambulatory but unable to work) | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 3 Participants | 8 Participants | 8 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 8 Participants | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 2 Participants | 7 Participants | 6 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Female | 13 Participants | 3 Participants | 5 Participants | 2 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 18 Participants | 0 Participants | 5 Participants | 8 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 1 | 4 / 7 | 3 / 10 | 4 / 12 |
| other Total, other adverse events | 3 / 3 | 1 / 1 | 7 / 7 | 10 / 10 | 10 / 10 |
| serious Total, serious adverse events | 0 / 3 | 1 / 1 | 3 / 7 | 6 / 10 | 6 / 10 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, defined as any of the following treatment-related events occurring within 4 weeks after the first dose of therapy: Any grade ≥ 3 nonhematologic toxicity, except: Grade 3 asymptomatic electrolyte abnormalities or hypophosphatemia for \< 24 hours; Grade 3 nausea, vomiting or diarrhea unless for \> 3 days despite optimal supportive care; Grade 3 fatigue for \< 14 days; Grade ≥ 3 hyperglycemia or toxicity attributed to dexamethasone and Grade ≥ 3 rash attributed to pomalidomide. Hematologic toxicities: * Grade 4 neutropenia: Absolute neutrophil count \< 0.5 × 10\^9/L for ≥ 7 days despite adequate growth factor support; febrile neutropenia * Thrombocytopenia: Grade 4 for ≥ 7 days, or Grade 4 for \< 7 days with grade 2 clinically significant bleeding or \< 10,000 platelets requiring transfusion, or Grade 3 with clinically significant bleeding or requiring platelet transfusion.
Time frame: Cycle 1, 28 days
Population: Participants who received at least 1 dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Any dose-limiting toxicity | 2 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Abdominal distension | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Gastric hemorrhage | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Mucosal inflammation | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Cognitive disorder | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Mucosal inflammation | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Abdominal distension | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Any dose-limiting toxicity | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Cognitive disorder | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Gastric hemorrhage | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Any dose-limiting toxicity | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Abdominal distension | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Gastric hemorrhage | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Cognitive disorder | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Mucosal inflammation | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Abdominal distension | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Cognitive disorder | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Any dose-limiting toxicity | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Gastric hemorrhage | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Dose-limiting Toxicities (DLTs) | Mucosal inflammation | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Dose-limiting Toxicities (DLTs) | Gastric hemorrhage | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Dose-limiting Toxicities (DLTs) | Any dose-limiting toxicity | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Dose-limiting Toxicities (DLTs) | Abdominal distension | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Dose-limiting Toxicities (DLTs) | Mucosal inflammation | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Dose-limiting Toxicities (DLTs) | Cognitive disorder | 0 Participants |
Primary
Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities
Laboratory abnormalities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Full chemistry panel included sodium, potassium, calcium, alkaline phosphatase, blood urea nitrogen, uric acid, lactate dehydrogenase, creatinine, chloride, bicarbonate, glucose, total protein, albumin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), phosphorous, and magnesium. Complete blood count (CBC) with differential included hemoglobin, hematocrit, white blood cell (WBC) count with complete manual or automated differential (total neutrophils, lymphocytes, monocytes, eosinophils, basophils; reported as absolute counts), red blood cell (RBC) count, and platelet count.
Time frame: Cycles 1 and 2 days 1, 5, 15, and 19 and days 3 and 8 of cycle 1, and day 1 of each cycle from cycle 3 thereafter until the end of treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively.
Population: Participants who received at least 1 dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | At least 1 Grade 3 or 4 laboratory toxicity | 2 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in total bilirubin | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in neutrophils | 2 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in sodium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in lymphocytes | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in magnesium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in lymphocytes | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in magnesium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in leukocytes | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in leukocytes | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in hemoglobin | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in platelets | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in neutrophils | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in glucose | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in sodium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 increase in glucose | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 increase in glucose | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in lymphocytes | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in lymphocytes | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in platelets | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in glucose | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in total bilirubin | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | At least 1 Grade 3 or 4 laboratory toxicity | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in magnesium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in magnesium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in sodium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in sodium | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in leukocytes | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in leukocytes | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in hemoglobin | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in neutrophils | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in neutrophils | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in neutrophils | 3 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in sodium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in sodium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in platelets | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in hemoglobin | 2 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in glucose | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in leukocytes | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in lymphocytes | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in lymphocytes | 5 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in leukocytes | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 increase in glucose | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | At least 1 Grade 3 or 4 laboratory toxicity | 6 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in magnesium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in neutrophils | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in magnesium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in total bilirubin | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in leukocytes | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in glucose | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in sodium | 3 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in total bilirubin | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in platelets | 2 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in neutrophils | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | At least 1 Grade 3 or 4 laboratory toxicity | 8 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in sodium | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in magnesium | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 increase in glucose | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in magnesium | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in hemoglobin | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in leukocytes | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in lymphocytes | 2 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in lymphocytes | 3 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in neutrophils | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in platelets | 5 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | At least 1 Grade 3 or 4 laboratory toxicity | 8 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in glucose | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 increase in glucose | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in total bilirubin | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 increase in magnesium | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in magnesium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in sodium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in sodium | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in hemoglobin | 3 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in leukocytes | 2 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in leukocytes | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in neutrophils | 4 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in neutrophils | 2 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 3 decrease in lymphocytes | 4 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Post-Baseline Grade 3 or 4 Laboratory Toxicities | Grade 4 decrease in lymphocytes | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Adverse events (AEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 and according to the following: Grade 1 = mild AE, Grade 2 = Moderate AE, Grade 3 = a severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. A serious AE is an event that met 1 or more of the following criteria: * Death * Life-threatening experience * 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 female subject or offspring of a female partner of a male subject * Important medical events that, based upon appropriate medical judgment, jeopardized the participant and may have required medical or surgical intervention to prevent an outcome listed above. Treatment-related AEs (TRAE) are those considered related to at least 1 study drug by the investigator.
Time frame: From first dose of any study drug up to 30 days after the last dose; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively.
Population: Participants who received at least 1 dose of any study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related fatal adverse events | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TRAEs leading to discontinuation of study drug | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious adverse events | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE Grade ≥ 3 | 2 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event | 3 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE Grade ≥ 3 | 2 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related treatment-emergent adverse events (TRAE) | 3 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Fatal adverse events | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE Grade ≥ 3 | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Fatal adverse events | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related treatment-emergent adverse events (TRAE) | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE Grade ≥ 3 | 1 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious adverse events | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TRAEs leading to discontinuation of study drug | 0 Participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related fatal adverse events | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related treatment-emergent adverse events (TRAE) | 7 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TRAEs leading to discontinuation of study drug | 1 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events | 3 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 2 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE Grade ≥ 3 | 5 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Fatal adverse events | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE Grade ≥ 3 | 4 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event | 7 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related fatal adverse events | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious adverse events | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE Grade ≥ 3 | 9 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related fatal adverse events | 0 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event | 10 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events | 6 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related treatment-emergent adverse events (TRAE) | 10 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious adverse events | 2 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TRAEs leading to discontinuation of study drug | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE Grade ≥ 3 | 6 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 1 Participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Fatal adverse events | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 4 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TRAEs leading to discontinuation of study drug | 4 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Fatal adverse events | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related treatment-emergent adverse events (TRAE) | 10 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related fatal adverse events | 0 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAE Grade ≥ 3 | 7 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event | 10 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related serious adverse events | 2 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events | 6 Participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAE Grade ≥ 3 | 9 Participants |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib
Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The area under the plasma concentration-time curve from time 0 to time infinity (AUCinf), estimated as the sum of AUClast and Clast/λz, where Clast is the last predicted concentration and λz is the first-order terminal rate constant estimated via linear regression of the terminal log-linear decay phase.
Time frame: Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose.
Population: Participants with adequate oprozomib plasma concentration-versus-time data to allow estimation of pharmacokinetic (PK) parameters. Treatment groups receiving the same dose of oprozomib were combined for PK analyses.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Cycle 1 day 1 | 2250 hr*ng/mL | — |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Cycle 1 day 1 | 3440 hr*ng/mL | Geometric Coefficient of Variation 96.1 |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Cycle 2 day 1 | 1830 hr*ng/mL | Geometric Coefficient of Variation 87.7 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Cycle 1 day 1 | 1660 hr*ng/mL | Geometric Coefficient of Variation 35.8 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time Infinity (AUCinf) of Oprozomib | Cycle 2 day 1 | 1900 hr*ng/mL | Geometric Coefficient of Variation 12.4 |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib
Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. The area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method.
Time frame: Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose.
Population: Participants with adequate oprozomib plasma concentration-versus-time data to allow estimation of pharmacokinetic (PK) parameters. Treatment groups receiving the same dose of oprozomib were combined for PK analyses.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 1 day 1 | 1090 hr*ng/mL | Geometric Coefficient of Variation 192.2 |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 2 day 1 | 446 hr*ng/mL | Geometric Coefficient of Variation 605.7 |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 1 day 1 | 1700 hr*ng/mL | Geometric Coefficient of Variation 145.9 |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 2 day 1 | 1860 hr*ng/mL | Geometric Coefficient of Variation 81.9 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 2 day 1 | 1800 hr*ng/mL | Geometric Coefficient of Variation 17.2 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of Oprozomib | Cycle 1 day 1 | 1730 hr*ng/mL | Geometric Coefficient of Variation 48.7 |
Secondary
Clinical Benefit Rate (CBR)
Clinical benefit rate is defined as the percentage of participants with a best overall response of minimal response (MR) per modified European Group for Blood and Marrow Transplantation criteria, or PR, VGPR, CR, or sCR as determined by the investigator according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). MR: * ≥ 25% but \< 49% reduction in serum M-protein and a 50 - 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg per 24 hours * If the serum and urine M-protein were not measurable, a decrease of 25 - 49% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. * For patients with nonsecretory myeloma only, 25 - 49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed * 25 - 49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination)
Time frame: Disease response was assessed every 4 weeks for the first 18 months and then every 8 weeks for the remainder of study treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively.
Population: Participants who received at least 1 dose of any study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Clinical Benefit Rate (CBR) | 33.3 percentage of participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Clinical Benefit Rate (CBR) | 100.0 percentage of participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Clinical Benefit Rate (CBR) | 85.7 percentage of participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Clinical Benefit Rate (CBR) | 60.0 percentage of participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Clinical Benefit Rate (CBR) | 60.0 percentage of participants |
Secondary
Maximum Plasma Concentration (Cmax) of Oprozomib
Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry.
Time frame: Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose.
Population: Participants with adequate oprozomib plasma concentration-versus-time data to allow estimation of pharmacokinetic (PK) parameters. Treatment groups receiving the same dose of oprozomib were combined for PK analyses.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 2 day 1 | 181 ng/mL | Geometric Coefficient of Variation 401.1 |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 1 day 1 | 492 ng/mL | Geometric Coefficient of Variation 398.3 |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 2 day 1 | 1030 ng/mL | Geometric Coefficient of Variation 91.5 |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 1 day 1 | 744 ng/mL | Geometric Coefficient of Variation 119.4 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 1 day 1 | 757 ng/mL | Geometric Coefficient of Variation 38.7 |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Maximum Plasma Concentration (Cmax) of Oprozomib | Cycle 2 day 1 | 965 ng/mL | Geometric Coefficient of Variation 44.4 |
Secondary
Overall Response Rate (ORR)
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. 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 the difference between involved and uninvolved free light chain levels (dFLC). A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. 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 serum FLC (SFLC), ≥ 90% decrease in dFLC. CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \<5% plasma cells in bone marrow (BM). Normal SFLC ratio if disease measurable only by SFLC. sCR: As for CR, and absence of clonal plasma cells in BM.
Time frame: Disease response was assessed every 4 weeks for the first 18 months and then every 8 weeks for the remainder of study treatment; median duration of treatment was 7.6, 28.0, 32.1, 46.3, and 17.4 weeks in each treatment group, respectively.
Population: Participants who received at least 1 dose of any study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Overall Response Rate (ORR) | 33.3 percentage of participants |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Overall Response Rate (ORR) | 100.0 percentage of participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Overall Response Rate (ORR) | 85.7 percentage of participants |
| Oprozomib 240 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Overall Response Rate (ORR) | 60.0 percentage of participants |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone: Expansion Phase | Overall Response Rate (ORR) | 60.0 percentage of participants |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Oprozomib
Oprozomib plasma concentrations were determined using liquid chromatography with tandem mass spectrometry.
Time frame: Cycle 1 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, 6, and 24 hours postdose. Cycle 2 day 1 at predose and 0.25, 0.5, 1, 2, 3, 4, and 6 hours postdose.
Population: Participants with adequate oprozomib plasma concentration-versus-time data to allow estimation of pharmacokinetic (PK) parameters. Treatment groups receiving the same dose of oprozomib were combined for PK analyses.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 1 day 1 | 1.0 hours |
| Oprozomib 150 mg 5/14 + Pomalidomide 4 mg + Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 2 day 1 | 4.0 hours |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 1 day 1 | 1.6 hours |
| Oprozomib 150 mg 5/14 + Pomalidomide 2 mg + Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 2 day 1 | 1.1 hours |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 1 day 1 | 2.2 hours |
| Oprozomib 210 mg 2/7 + Pomalidomide 4 mg + Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Oprozomib | Cycle 2 day 1 | 1.1 hours |