Multiple Myeloma
Conditions
Keywords
Cancer, Multiple Myeloma (MM), Relapsed or Refractory (R/R), Venetoclax, Pomalidomide, Dexamethasone
Brief summary
This was an open-label, multicenter study designed to evaluate the safety and preliminary efficacy of venetoclax combined with pomalidomide and dexamethasone in participants with relapsed or refractory (R/R) multiple myeloma (MM) who received at least 1 prior line of therapy with documented evidence of progression during or after the participant's last treatment regimen. The study was designed to consist of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). For Part 2 the participants were to be divided into 2 cohorts, participants positive for t(11;14) translocation and participants negative for t(11;14) translocation.
Detailed description
Following communication of the results of the primary progression-free survival (PFS) analysis from the Phase 3 BELLINI study (Study M14-031; NCT02755597), the company-sponsored MM studies were placed on partial clinical hold (PCH) in March 2019 by the United States (US) Food and Drug Administration and enrollment was halted. The sponsor did not pursue release of the PCH for this study; therefore, enrollment was not re-opened. In accordance with the terms of the PCH, participants who were deriving clinical benefit were allowed to continue to receive treatment. One participant was still active in Part 1 of the study when the sponsor decided not to pursue release of the PCH (in January 2020) and, therefore, continued to receive treatment and have regular assessments until disease progression. The study was discontinued when the last participant completed study treatment. No participants were enrolled in Part 2 of the study.
Interventions
DRUGVenetoclax
Tablet; oral
DRUGPomalidomide
Capsule; oral
DRUGDexamethasone
Administered orally; for participants over 75 years of age, dexamethasone could have been administered at a 20 mg dose \[qw\]
Sponsors
Celgene
AbbVie
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
* Relapsed or refractory (R/R) multiple myeloma (MM) with documented evidence of progression during or after the participant's last treatment regimen * Measurable disease as described in the protocol * Received at least 1 prior line of therapy as described in the protocol * Must meet prior antimyeloma treatment parameters, as described in the protocol, and includes: * Received at least 2 consecutive cycles of lenalidomide or a lenalidomide-containing regimen * Refractory to lenalidomide * Exposed to a proteasome inhibitor (PI) alone or in combination with another agent * Had a response of partial response (PR) or better to prior therapy based on the investigator's determination of response as defined by International Myeloma Working Group (IMWG) criteria * Has t(11;14) status as described in the protocol and meets the following criteria: * For Part 1: MM participants independent of cytogenetic profile * For Part 2, Arm A: participant must be t(11;14) positive * For Part 2, Arm B: participant must be t(11;14) negative * An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Adequate kidney, liver and hematologic laboratory values
Exclusion criteria
* Previous treatment with venetoclax or other BCL-2 inhibitors, or previous treatment with pomalidomide * Known sensitivity to any IMiDs * Allogenic or syngeneic stem cell transplant within 6 months before the first dose of study drug or active ongoing graft versus host disease * Autologous stem cell transplant within 12 weeks before the first dose of study drug * Known meningeal involvement of MM
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From first dose of study drug until 30 days following last dose of study drug (up to 70 weeks) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section. |
| Overall Response Rate (ORR) | Approximately 15 months | ORR is defined as the percentage of participants experiencing a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) using the International Myeloma Working Group (IMWG) 2016 criteria for disease response and progression. CR= negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal serum free light chain (FLC) ratio and absence of clonal cells in bone marrow; VGPR= serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hours; PR= ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Approximately 20 months | PFS is defined as the number of days from the date of first dose of any study drug to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug. |
| Duration of Response (DOR) | Approximately 15 months | DOR for a given participant is defined as the number of days from the date of that participant's first documented response (Partial Response \[PR\] or better) to the date of first documented disease progression (PD) or death due to multiple myeloma (MM), whichever occurs first. If the participant with a documented response did not have an event of PD and the participant had not died due to MM, the participant's data was to be censored. |
| Time-to-progression (TTP) | Approximately 15 months | TTP for a given participant is defined as the number of days from the date of first dose to the date of first documented disease progression (PD) or death due to multiple myeloma (MM), whichever occurs first. If the participant did not have an event of PD and the participant had not died due to MM, the participant's data was to be censored. |
Countries
Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Full Analysis Set: participants who received at least 1 dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| Participants Positive for t(11;14) Translocation Participants positive for t(11;14) translocation who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg) | 3 |
| Participants Negative for t(11;14) Translocation Participants negative for t(11;14) translocation who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg) | 5 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 4 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Participants Negative for t(11;14) Translocation | Total | Participants Positive for t(11;14) Translocation |
|---|---|---|---|
| Age, Continuous | 66.0 years | 67.5 years | 68.0 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black/African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 0 / 5 |
| other Total, other adverse events | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 3 / 3 | 2 / 5 |
Outcome results
Primary
Number of Participants With Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs/TESAEs) are defined as any event that began or worsened in severity after the first dose of study drug. For more details on adverse events please see the Adverse Event section.
Time frame: From first dose of study drug until 30 days following last dose of study drug (up to 70 weeks)
Population: Safety Analysis Set: participants who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Participants Positive for t(11;14) Translocation | Number of Participants With Adverse Events | Any TEAE | 3 Participants |
| Participants Positive for t(11;14) Translocation | Number of Participants With Adverse Events | TESAE | 3 Participants |
| Participants Negative for t(11;14) Translocation | Number of Participants With Adverse Events | Any TEAE | 5 Participants |
| Participants Negative for t(11;14) Translocation | Number of Participants With Adverse Events | TESAE | 2 Participants |
Primary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants experiencing a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) using the International Myeloma Working Group (IMWG) 2016 criteria for disease response and progression. CR= negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal serum free light chain (FLC) ratio and absence of clonal cells in bone marrow; VGPR= serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hours; PR= ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours.
Time frame: Approximately 15 months
Population: Full Analysis Set: participants who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants Positive for t(11;14) Translocation | Overall Response Rate (ORR) | 66.7 percentage of participants |
| Participants Negative for t(11;14) Translocation | Overall Response Rate (ORR) | 60.0 percentage of participants |
| All Participants | Overall Response Rate (ORR) | 62.5 percentage of participants |
Secondary
Duration of Response (DOR)
DOR for a given participant is defined as the number of days from the date of that participant's first documented response (Partial Response \[PR\] or better) to the date of first documented disease progression (PD) or death due to multiple myeloma (MM), whichever occurs first. If the participant with a documented response did not have an event of PD and the participant had not died due to MM, the participant's data was to be censored.
Time frame: Approximately 15 months
Population: Full Analysis Set: participants who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg) and had disease progression or death due to multiple myeloma
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants Positive for t(11;14) Translocation | Duration of Response (DOR) | 393.0 days |
| Participants Negative for t(11;14) Translocation | Duration of Response (DOR) | NA days |
| All Participants | Duration of Response (DOR) | 393.0 days |
Secondary
Progression-Free Survival (PFS)
PFS is defined as the number of days from the date of first dose of any study drug to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug.
Time frame: Approximately 20 months
Population: Full Analysis Set: participants who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants Positive for t(11;14) Translocation | Progression-Free Survival (PFS) | 220.0 days |
| Participants Negative for t(11;14) Translocation | Progression-Free Survival (PFS) | NA days |
| All Participants | Progression-Free Survival (PFS) | 320.0 days |
Secondary
Time-to-progression (TTP)
TTP for a given participant is defined as the number of days from the date of first dose to the date of first documented disease progression (PD) or death due to multiple myeloma (MM), whichever occurs first. If the participant did not have an event of PD and the participant had not died due to MM, the participant's data was to be censored.
Time frame: Approximately 15 months
Population: Full Analysis Set: participants who received at least 1 dose of study drug (venetoclax 400 mg, pomalidomide 4 mg, and dexamethasone 40 mg) and had disease progression or death due to multiple myeloma
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants Positive for t(11;14) Translocation | Time-to-progression (TTP) | 420.0 days |
| Participants Negative for t(11;14) Translocation | Time-to-progression (TTP) | NA days |
| All Participants | Time-to-progression (TTP) | 420.0 days |