Multiple Myeloma
Conditions
Keywords
PDL1, PD1, Multiple Myeloma
Brief summary
The purpose of this study is to compare the efficacy of pomalidomide and low dose dexamethasone with pembrolizumab (MK-3475) to that of pomalidomide and low dose dexamethasone without pembrolizumab in terms of Progression-Free Survival (PFS) in participants with refractory or relapsed and refractory multiple myeloma (rrMM) who have undergone at least 2 lines of prior treatment. The study's 2 primary hypotheses are: 1. Pembrolizumab in combination with pomalidomide and low dose dexamethasone prolongs PFS as assessed by Clinical Adjudication Committee (CAC) blinded central review using International Myeloma Working Group Criteria for Response Assessment in Multiple Myeloma (IMWG) criteria compared to treatment with pomalidomide and low dose dexamethasone standard of care (SOC) alone. 2. Pembrolizumab in combination with pomalidomide and low dose dexamethasone prolongs OS compared to treatment with pomalidomide and low dose dexamethasone (SOC) alone.
Interventions
BIOLOGICALPembrolizumab
pembrolizumab 200 mg IV infusion
DRUGPomalidomide
pomalidomide 4 mg capsules
DRUGDexamethasone
dexamethasone 40 mg tablets
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a confirmed diagnosis of active multiple myeloma and measurable disease * Must have undergone prior treatment with ≥2 treatment lines of anti-myeloma therapy and must have failed last line of treatment (refractory to last line of treatment) * Prior anti-myeloma treatments must have included an immunomodulatory drug (IMiD) AND proteasome inhibitor alone or in combination and participant must have failed therapy with an IMiD OR proteasome inhibitor * Has performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale * Female participants of childbearing potential must have 2 negative urine human chorionic gonadotropin tests within 10 to 14 days and within 24 hours prior to receiving study medication * Female participants of childbearing potential and male participants must agree to use adequate contraception 28 days prior to study start and continuing for up to 28 days after the last dose of pomalidomide (or 120 days after the last dose of pembrolizumab)
Exclusion criteria
* Has had prior anti-myeloma therapy within 2 weeks prior to study start and has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events due to a previously administered agent * Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of Graft versus Host Disease \[GVHD\]). * Has received autologous stem cell transplant (auto-SCT) within 12 weeks before the first infusion or is planning for or is eligible for auto-SCT * Has received previous therapy with pomalidomide * Has peripheral neuropathy ≥ Grade 2 * Has a known additional malignancy that is progressing or requires active treatment within the last 5 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy) * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis * Has received prior therapy with an anti-programmed cell death 1 receptor (anti-PD-1), antiprogrammed death-ligand 1 (anti-PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways) * Is pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Assessed by Clinical Adjudication Committee (CAC) Blinded Central Review According to the International Myeloma Working Group (IMWG) Response Criteria | Up to approximately 30 months | Progression free survival was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. PFS was assessed by CAC blinded central review according to the IMWG criteria based on the development of new bone lesions or soft tissue plasmacytomas or on a definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Median PFS was calculated from the product-limit (Kaplan-Meier) method for censored data. The database cutoff date was July 9, 2018. |
| Overall Survival (OS) | Up to approximately 54 months | Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Median overall survival was calculated from the product-limit (Kaplan-Meier) method for censored data. The database cutoff date was August 3, 2020. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants Discontinuing Study Investigational Product Due to an AE | Up to approximately 54 months | An adverse event was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Database cutoff was August 3, 2020. |
| Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | Up to approximately 30 months | ORR was defined as the percentage of the participants in the analysis population who achieved at least a partial response (stringent complete response \[sCR\]+complete response \[CR\]+very good partial response \[VGPR\]+partial response \[PR\]) according to the IMWG. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. The database cutoff date was July 9, 2018. |
| Second Progression Free Survival (PFS2) | Up to approximately 30 months | PFS2 was defined as the time from randomization to subsequent disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever occurred first, by investigator assessment. As a result of a full clinical hold by FDA that led to discontinuation of study enrollment, no data was collected for analysis of PFS2. |
| Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | Up to approximately 30 months | Disease control rate was the percentage of participants who achieved confirmed sCR, CR, VGPR, PR, minimal response (MR) or have demonstrated stable disease (SD) for at least 12 weeks prior to any evidence of progression. PD was development of or an increase in the size of bone lesions or soft tissue plasmacytomas. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum FLC assay ratio and absence of clonal cells in bone marrow by immunohistochemistry/fluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. The data cutoff date was July 9, 2018. |
| Participants Experiencing One or More Adverse Events (AEs) | Up to approximately 54 months | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Database cutoff was August 3, 2020. |
Participant flow
Recruitment details
Subject Disposition as per database cutoff date of August 3, 2020.
Pre-assignment details
Note: For administrative reasons (a noncompliant site), one participant in the SOC arm was recorded as Ongoing in Trial in the CSR Disposition Table and Final Disposition Unknown here.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 every 3 weeks (Q3W) PLUS pomalidomide 4 mg orally (PO) on Days 1 to 21 of each 28-day cycle PLUS dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle. | 126 |
| Standard of Care (SOC) Pomalidomide+Dexamethasone Participants receive pomalidomide 4 mg PO on Days 1 to 21 of each 28-day cycle PLUS dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle. | 125 |
| Total | 251 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 2 |
| Overall Study | Death | 73 | 60 |
| Overall Study | Final Disposition Unknown | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Progressive Disease | 0 | 1 |
| Overall Study | Screen failure | 1 | 0 |
| Overall Study | Study Terminated at Selected Sites | 27 | 50 |
| Overall Study | Withdrawal by Subject | 11 | 11 |
Baseline characteristics
| Characteristic | Standard of Care (SOC) Pomalidomide+Dexamethasone | Pembrolizumab+Pomalidomide+Dexamethasone | Total |
|---|---|---|---|
| Age, Continuous | 66.4 Years STANDARD_DEVIATION 10 | 65.5 Years STANDARD_DEVIATION 9.3 | 65.9 Years STANDARD_DEVIATION 9.6 |
| Disease Status (Refractory vs. Sensitive to Lenalidomide) Refractory to Lenalidomide | 108 Participants | 108 Participants | 216 Participants |
| Disease Status (Refractory vs. Sensitive to Lenalidomide) Sensitive to Lenalidomide | 17 Participants | 18 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 8 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 117 Participants | 110 Participants | 227 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 17 Participants | 29 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 10 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) White | 95 Participants | 92 Participants | 187 Participants |
| Sex: Female, Male Female | 46 Participants | 48 Participants | 94 Participants |
| Sex: Female, Male Male | 79 Participants | 78 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 86 / 126 | 64 / 125 |
| other Total, other adverse events | 115 / 122 | 114 / 123 |
| serious Total, serious adverse events | 79 / 122 | 57 / 123 |
Outcome results
Primary
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Median overall survival was calculated from the product-limit (Kaplan-Meier) method for censored data. The database cutoff date was August 3, 2020.
Time frame: Up to approximately 54 months
Population: The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone | Overall Survival (OS) | 21.0 Months |
| Standard of Care (SOC) Pomalidomide+Dexamethasone | Overall Survival (OS) | 39.6 Months |
p-value: 0.9998995% CI: [1.32, 2.55]Log Rank
Primary
Progression Free Survival (PFS) Assessed by Clinical Adjudication Committee (CAC) Blinded Central Review According to the International Myeloma Working Group (IMWG) Response Criteria
Progression free survival was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. PFS was assessed by CAC blinded central review according to the IMWG criteria based on the development of new bone lesions or soft tissue plasmacytomas or on a definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Median PFS was calculated from the product-limit (Kaplan-Meier) method for censored data. The database cutoff date was July 9, 2018.
Time frame: Up to approximately 30 months
Population: The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone | Progression Free Survival (PFS) Assessed by Clinical Adjudication Committee (CAC) Blinded Central Review According to the International Myeloma Working Group (IMWG) Response Criteria | 5.7 Months |
| Standard of Care (SOC) Pomalidomide+Dexamethasone | Progression Free Survival (PFS) Assessed by Clinical Adjudication Committee (CAC) Blinded Central Review According to the International Myeloma Working Group (IMWG) Response Criteria | 7.4 Months |
p-value: 0.9932495% CI: [1.08, 2.08]Log Rank
Secondary
Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review
Disease control rate was the percentage of participants who achieved confirmed sCR, CR, VGPR, PR, minimal response (MR) or have demonstrated stable disease (SD) for at least 12 weeks prior to any evidence of progression. PD was development of or an increase in the size of bone lesions or soft tissue plasmacytomas. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum FLC assay ratio and absence of clonal cells in bone marrow by immunohistochemistry/fluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. The data cutoff date was July 9, 2018.
Time frame: Up to approximately 30 months
Population: The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone | Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 88.1 Percentage of participants |
| Standard of Care (SOC) Pomalidomide+Dexamethasone | Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 84.8 Percentage of participants |
Secondary
Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review
ORR was defined as the percentage of the participants in the analysis population who achieved at least a partial response (stringent complete response \[sCR\]+complete response \[CR\]+very good partial response \[VGPR\]+partial response \[PR\]) according to the IMWG. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 hours. The database cutoff date was July 9, 2018.
Time frame: Up to approximately 30 months
Population: The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone | Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 37.3 Percentage of participants |
| Standard of Care (SOC) Pomalidomide+Dexamethasone | Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 42.4 Percentage of participants |
p-value: 0.7992195% CI: [-17.1, 6.9]Miettinen & Nurminen method
Secondary
Participants Discontinuing Study Investigational Product Due to an AE
An adverse event was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Database cutoff was August 3, 2020.
Time frame: Up to approximately 54 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone | Participants Discontinuing Study Investigational Product Due to an AE | 26 Participants |
| Standard of Care (SOC) Pomalidomide+Dexamethasone | Participants Discontinuing Study Investigational Product Due to an AE | 10 Participants |
Secondary
Participants Experiencing One or More Adverse Events (AEs)
An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Database cutoff was August 3, 2020.
Time frame: Up to approximately 54 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab+Pomalidomide+Dexamethasone | Participants Experiencing One or More Adverse Events (AEs) | 122 Participants |
| Standard of Care (SOC) Pomalidomide+Dexamethasone | Participants Experiencing One or More Adverse Events (AEs) | 119 Participants |
Secondary
Second Progression Free Survival (PFS2)
PFS2 was defined as the time from randomization to subsequent disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever occurred first, by investigator assessment. As a result of a full clinical hold by FDA that led to discontinuation of study enrollment, no data was collected for analysis of PFS2.
Time frame: Up to approximately 30 months
Population: The analysis population was to include all randomized participants. Study treatment was terminated early and no data was collected for analysis of PFS2.