Multiple Myeloma
Conditions
Keywords
PD1, PD-1, PD-L1, PDL1
Brief summary
The purpose of this study is to compare the efficacy of lenalidomide and low dose dexamethasone with pembrolizumab (MK-3475) to that of lenalidomide and low dose dexamethasone without pembrolizumab in terms of progression-free survival (PFS) in participants with newly diagnosed and treatment-naïve multiple myeloma who are ineligible for autologous stem cell transplant (Auto-SCT). The study's primary hypothesis is that pembrolizumab in dexamethasone prolongs progression free survival (PFS) as assessed by Clinical Adjudication Committee (CAC) blinded central review using International Myeloma Working Group (IMWG) response criteria compared to treatment combination with lenalidomide and low-dose with lenalidomide and low-dose dexamethasone (standard of care, SOC) alone.
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGLenalidomide
oral capsules
DRUGDexamethasone
oral 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
* Confirmed diagnosis of active multiple myeloma and measurable disease. * Ineligible to receive treatment with auto-SCT due to age (≥65 years old) or any significant coexisting medical condition (cardiac, renal, pulmonary or hepatic dysfunction), likely to have a negative impact on tolerability of auto-SCT. Participants \<65 years of age who refuse auto-SCT are not eligible for this study. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. * Female participants of childbearing potential must have 2 negative urine pregnancy tests (with a sensitivity of at least 25 Milli-international units/milliliter) within 10 to 14 days and within 24 hours prior to receiving study medication. * Female participants of childbearing potential must agree to use adequate contraception 28 days prior to study start, continuing throughout the study, and for up to 28 days after the last dose of lenalidomide (or 120 days after the last dose of pembrolizumab). * Male participants of childbearing potential must agree to use adequate contraception from the first dose of study medication, continuing throughout the study, and for up to 28 days after the last dose of lenalidomide (or 120 days after the last dose of pembrolizumab).
Exclusion criteria
* Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. * 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 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), anti-programmed 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 co-stimulation or checkpoint pathways). * Has a known Human Immunodeficiency Virus (HIV), or a known, active Hepatitis B (HBV), or a known, active Hepatitis C (HCV) infection. * Is unable or unwilling to undergo thromboembolic prophylaxis including, as clinically indicated, aspirin, Coumadin (warfarin) or low-molecular weight heparin. * Has lactose intolerance. * Has an invasive fungal infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) Response Criteria 2011 by Clinical Adjudication Committee (CAC) Blinded Central Review | Up to approximately 30 months | PFS was defined as the time from randomization to the first documented disease progression (events of new bone lesions, soft tissue plasmacytomas or an increase in existing lesions, or death due to any cause). The median PFS was calculated from the product-limit (Kaplan-Meier) method for censored data. Due to the small number of events, the tail of the estimated survival distribution was close to the median for both arms. The higher variability of the tail estimates resulted in observing the median estimate in the experimental arm but not in the standard of care arm even when number of events in 2 arms were similar. The database cutoff date was July 9, 2018. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | Up to approximately 30 months | ORR was based on participants 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 data cutoff date was July 9, 2018. |
| Duration of Response (DOR) Evaluated According to IMWG Response Criteria by CAC Blinded Central Review | Up to approximately 30 months | Response duration was defined as the time from first documented evidence of at least a partial response (sCR+CR+VGPR+PR\]), until confirmed disease progression or death. DOR was calculated from product-limit (Kaplan-Meier) method for censored data. This is an event-driven (events of disease progression and death) outcome measure. At the time of data cut-off, there were an insufficient number of events from the censored data to be able to estimate certain parameters (e.g. medians). Full Range is the minimum and maximum of the observed duration of response. The data cutoff date was July 9, 2018. |
| 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 defined as the percentage of participants who achieved confirmed sCR, CR, VGPR, PR, or have demonstrated SD for at least 12 weeks prior to any evidence of progression. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; 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; SD = not meeting the criteria for CR, VGPR, PR, or PD; PD = 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. Data cutoff date was July 9, 2018. |
| Overall Survival (OS) | Up to approximately 55 months | OS was defined as the time from randomization to death due to any cause. OS was calculated from the product-limit (Kaplan-Meier) method for censored data. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. This is an event-driven (events of death) outcome measure. At the time of data cut-off, there were an insufficient number of events from the censored data to be able to estimate certain parameters (e.g. medians). The database cutoff date was August 3, 2020. |
| Number of Participants Who Experienced One or More Adverse Events (AEs) | Up to approximately 55 months | An 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. The database cutoff date was August 3, 2020. |
| Number of Participants Discontinuing Study Treatment Due to an AE | Up to approximately 55 months | An 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. The database cutoff date was August 3, 2020. |
| Second Progression Free Survival (PFS2) | Up to approximately 55 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. PFS was assessed by Clinical Adjudication Committee (CAC) blinded central review according to the IMWG response 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. PFS2 was not completed due to incomplete enrollment for a clinical hold and study cancellation. |
Participant flow
Recruitment details
This study was conducted at 140 centers in 15 countries. The database cutoff date was August 3, 2020.
Pre-assignment details
Note: Due to administrative reasons (a noncompliant site), 2 participants in the Pembrolizumab plus SOC arm and one participant in the SOC arm, were recorded as Ongoing in Trial in the CSR Disposition Table and Final Disposition Unknown here.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Lenalidomide + Dexamethasone Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS lenalidomide 25 mg orally (PO) on Days 1 to 21 of each 21-day treatment cycle, and dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle for up to 18 cycles. | 156 |
| Lenolidomide + Dexamethasone Participants received lenalidomide 25 mg PO on Days 1 to 21 of each 21-day treatment cycle, and dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle for up to 18 cycles. | 154 |
| Total | 310 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 18 | 11 |
| Overall Study | Death | 31 | 29 |
| Overall Study | Final Disposition Unknown | 2 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Screen Failure | 0 | 2 |
| Overall Study | Study Terminated at Selected Sites | 82 | 88 |
| Overall Study | Withdrawal by Subject | 20 | 20 |
Baseline characteristics
| Characteristic | Pembrolizumab + Lenalidomide + Dexamethasone | Lenolidomide + Dexamethasone | Total |
|---|---|---|---|
| Age, Continuous | 74.4 Years STANDARD_DEVIATION 6 | 74.3 Years STANDARD_DEVIATION 5.9 | 74.3 Years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 143 Participants | 136 Participants | 279 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 14 Participants | 23 Participants |
| International Stage (I, II, III). Missing | 1 Participants | 1 Participants | 2 Participants |
| International Stage (I, II, III). Stage I | 39 Participants | 53 Participants | 92 Participants |
| International Stage (I, II, III). Stage II | 70 Participants | 66 Participants | 136 Participants |
| International Stage (I, II, III). Stage III | 46 Participants | 34 Participants | 80 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 27 Participants | 27 Participants | 54 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) White | 115 Participants | 121 Participants | 236 Participants |
| Sex: Female, Male Female | 85 Participants | 81 Participants | 166 Participants |
| Sex: Female, Male Male | 71 Participants | 73 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 51 / 156 | 43 / 154 |
| other Total, other adverse events | 143 / 154 | 129 / 148 |
| serious Total, serious adverse events | 91 / 154 | 65 / 148 |
Outcome results
Primary
Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) Response Criteria 2011 by Clinical Adjudication Committee (CAC) Blinded Central Review
PFS was defined as the time from randomization to the first documented disease progression (events of new bone lesions, soft tissue plasmacytomas or an increase in existing lesions, or death due to any cause). The median PFS was calculated from the product-limit (Kaplan-Meier) method for censored data. Due to the small number of events, the tail of the estimated survival distribution was close to the median for both arms. The higher variability of the tail estimates resulted in observing the median estimate in the experimental arm but not in the standard of care arm even when number of events in 2 arms were similar. 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 + Lenalidomide + Dexamethasone | Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) Response Criteria 2011 by Clinical Adjudication Committee (CAC) Blinded Central Review | 19.6 Months |
| Lenolidomide + Dexamethasone | Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) Response Criteria 2011 by Clinical Adjudication Committee (CAC) Blinded Central Review | NA Months |
p-value: 0.3347595% CI: [0.56, 1.45]Log Rank
Secondary
Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review
Disease control rate was defined as the percentage of participants who achieved confirmed sCR, CR, VGPR, PR, or have demonstrated SD for at least 12 weeks prior to any evidence of progression. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; 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; SD = not meeting the criteria for CR, VGPR, PR, or PD; PD = 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. 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 + Lenalidomide + Dexamethasone | Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 89.1 Percentage of participants |
| Lenolidomide + Dexamethasone | Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 91.6 Percentage of participants |
Secondary
Duration of Response (DOR) Evaluated According to IMWG Response Criteria by CAC Blinded Central Review
Response duration was defined as the time from first documented evidence of at least a partial response (sCR+CR+VGPR+PR\]), until confirmed disease progression or death. DOR was calculated from product-limit (Kaplan-Meier) method for censored data. This is an event-driven (events of disease progression and death) outcome measure. At the time of data cut-off, there were an insufficient number of events from the censored data to be able to estimate certain parameters (e.g. medians). Full Range is the minimum and maximum of the observed duration of response. The data cutoff date was July 9, 2018.
Time frame: Up to approximately 30 months
Population: The analysis population included all randomized participants who demonstrated at least a partial response. Participants were included in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenalidomide + Dexamethasone | Duration of Response (DOR) Evaluated According to IMWG Response Criteria by CAC Blinded Central Review | NA Months |
| Lenolidomide + Dexamethasone | Duration of Response (DOR) Evaluated According to IMWG Response Criteria by CAC Blinded Central Review | NA Months |
Secondary
Number of Participants Discontinuing Study Treatment Due to an AE
An 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. The database cutoff date was August 3, 2020.
Time frame: Up to approximately 55 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Lenalidomide + Dexamethasone | Number of Participants Discontinuing Study Treatment Due to an AE | 44 Participants |
| Lenolidomide + Dexamethasone | Number of Participants Discontinuing Study Treatment Due to an AE | 26 Participants |
Secondary
Number of Participants Who Experienced One or More Adverse Events (AEs)
An 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. The database cutoff date was August 3, 2020.
Time frame: Up to approximately 55 months
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Lenalidomide + Dexamethasone | Number of Participants Who Experienced One or More Adverse Events (AEs) | 152 Participants |
| Lenolidomide + Dexamethasone | Number of Participants Who Experienced One or More Adverse Events (AEs) | 141 Participants |
Secondary
Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review
ORR was based on participants 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 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 + Lenalidomide + Dexamethasone | Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 74.4 Percentage of participants |
| Lenolidomide + Dexamethasone | Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review | 68.8 Percentage of participants |
p-value: 0.1310295% CI: [-4.3, 15.8]One-sided p-value for testing
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. OS was calculated from the product-limit (Kaplan-Meier) method for censored data. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. This is an event-driven (events of death) outcome measure. At the time of data cut-off, there were an insufficient number of events from the censored data to be able to estimate certain parameters (e.g. medians). The database cutoff date was August 3, 2020.
Time frame: Up to approximately 55 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 + Lenalidomide + Dexamethasone | Overall Survival (OS) | NA Months |
| Lenolidomide + Dexamethasone | Overall Survival (OS) | NA Months |
p-value: 0.8341695% CI: [0.81, 1.84]Stratified log-rank test
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. PFS was assessed by Clinical Adjudication Committee (CAC) blinded central review according to the IMWG response 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. PFS2 was not completed due to incomplete enrollment for a clinical hold and study cancellation.
Time frame: Up to approximately 55 months
Population: The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized. PFS2 was not completed due to incomplete enrollment for a clinical hold and study cancellation.