Multiple Myeloma
Conditions
Keywords
Multiple myeloma, Daratumumab, Proteasome inhibitor, Immunomodulatory drug, IMiD
Brief summary
The purpose of this study is to evaluate the efficacy and safety of 2 daratumumab treatment regimens in participants with multiple myeloma who have received at least 3 prior lines of therapy (including a proteasome inhibitor \[PI\] and immunomodulatory drug \[IMiD\]) or are double refractory to a PI and an IMiD.
Detailed description
This is an open-label (identity of assigned study drug will be known) study of daratumumab for the treatment of participants with multiple myeloma who have received at least 3 prior lines of therapy including a PI and an IMiD or whose disease is double refractory to both a PI and an IMiD. Up to approximately 150 participants are to be enrolled. The study includes screening, treatment, and follow-up phases. Participants will receive daratumumab by intravenous infusion (28-day cycles) until disease progression, unacceptable toxicity, or other protocol-defined reasons. For all study drug administrations, participants will receive pre- and post-infusion medications for the prevention of infusion related reactions. Follow-up will continue until death, loss to follow up, consent withdrawal for study participation, or study end, whichever occurs first. The study will consist of 2 sequential parts (Part 1 and Part 2). The purpose of Part 1 is to select a dose and schedule for Part 2 of the study. Assessment of tumor response and disease progression will be conducted according to IMWG response criteria. Serial pharmacokinetic blood samples and a pharmacogenomic blood sample will be collected. Safety will be monitored throughout the study. At the end of the study, participants who are benefiting from treatment with daratumumab will have the option to continue treatment.
Interventions
DRUGDaratumumab 16 mg/kg (Part 1)
Daratumumab 16 mg/kg administered at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter by intravenous infusion
DRUGDaratumumab 8 mg/kg (Part 1)
Daratumumab 8 mg/kg every 4 weeks (Q4W) continuously by intravenous infusion
DRUGMethylprednisolone
Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted
DRUGAcetaminophen
650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration.
DRUGDiphenhydramine
25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration.
DRUGDaratumumab (Part 2)
Based on the Part 1 response rate, Group A or B treatment will be selected as the treatment regimen for participants enrolled in Part 2.
Sponsors
Janssen Research & Development, 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
* Documented multiple myeloma according to protocol-defined criteria * Evidence of disease progression on the most recent prior treatment regimen based on International Myeloma Working Group criteria * Eastern Cooperative Oncology Group performance status score of 0, 1, or 2 * Laboratory values and electrocardiogram within protocol-defined parameters at screening
Exclusion criteria
* Received daratumumab or other anti-CD38 therapies previously * Nonsecretory multiple myeloma * Previously received an allogenic stem cell transplant or has received an autologous stem cell transplantation within 12 weeks * Exhibiting clinical signs of meningeal involvement of multiple myeloma * Known chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years * Seropositive for human immunodeficiency virus, hepatitis B or antibodies to hepatitis B surface and core antigens, or hepatitis C * Has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response | Up to 14.4 Months | Overall response defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Per IMWG criteria, sCR: is defined as normal free light chain (FLC) ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5 % plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>= 90% reduction in serum M-protein plus urine M-protein level \< 100mg/24 hours; PR: \>= 50 % reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>= 90% or to \<200 mg/24 hours; if the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Approximately up to 3 years | Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method. |
| Percentage of Participants With Clinical Benefit | Up to 14.4 Months | Clinical benefit rate defined as percentage of participants who achieved minimal response (MR) or better. MR: \>=25% but \<= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%. If present at baseline 25% to 49% reduction in size of soft tissue plasmacytomas. |
| Duration of Response | Up to 14.4 Months | Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in IMWG criteria. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component (the absolute increase must be \>=0.5 g/dL) and/or; urine M-component (the absolute increase must be \>=200 mg/24 hours) and/or; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be \>10 milligram per deciliter (mg/dL); Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.65 millimole per liter \[mmol/L\]) that can be attributed solely to the plasma cell proliferative disorder. |
| Progression Free Survival | Up to 14.4 Months | Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first. |
| Time to Disease Progression | Up to 14.4 Months | Time to progression was defined as the number of days from the date of first dose of daratumumab to the date of first record of disease progression. |
| Time to Response | Up to 14.4 Months | Time to response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better). |
Countries
Canada, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daratumumab 8 mg/kg Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity. | 18 |
| Daratumumab 16 mg/kg Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity. | 106 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 69 |
| Overall Study | Lost to Follow-up | 0 | 8 |
| Overall Study | Study Terminated By Sponsor | 1 | 22 |
| Overall Study | Withdrawal by Subject | 2 | 7 |
Baseline characteristics
| Characteristic | Daratumumab 8 mg/kg | Daratumumab 16 mg/kg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 48 Participants | 58 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 58 Participants | 66 Participants |
| Age, Continuous | 64.2 years STANDARD_DEVIATION 7.72 | 62.9 years STANDARD_DEVIATION 10 | 63.1 years STANDARD_DEVIATION 9.68 |
| Number of Prior Lines of Therapy <= 3 Lines | 6 Participants | 19 Participants | 25 Participants |
| Number of Prior Lines of Therapy > 3 Lines | 12 Participants | 87 Participants | 99 Participants |
| Refractory to Proteasome Inhibitor (PI)/ Immunomodulatory Drug (IMiD) Both a PI and IMiD | 15 Participants | 101 Participants | 116 Participants |
| Refractory to Proteasome Inhibitor (PI)/ Immunomodulatory Drug (IMiD) IMiD only | 0 Participants | 1 Participants | 1 Participants |
| Refractory to Proteasome Inhibitor (PI)/ Immunomodulatory Drug (IMiD) None | 2 Participants | 1 Participants | 3 Participants |
| Refractory to Proteasome Inhibitor (PI)/ Immunomodulatory Drug (IMiD) PI only | 1 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Canada | 0 Participants | 22 Participants | 22 Participants |
| Region of Enrollment Spain | 3 Participants | 9 Participants | 12 Participants |
| Region of Enrollment United States | 15 Participants | 75 Participants | 90 Participants |
| Sex: Female, Male Female | 6 Participants | 54 Participants | 60 Participants |
| Sex: Female, Male Male | 12 Participants | 52 Participants | 64 Participants |
| Stage of Disease (ISS) I | 2 Participants | 26 Participants | 28 Participants |
| Stage of Disease (ISS) II | 8 Participants | 40 Participants | 48 Participants |
| Stage of Disease (ISS) III | 8 Participants | 40 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 18 | 105 / 106 |
| serious Total, serious adverse events | 6 / 18 | 33 / 106 |
Outcome results
Primary
Percentage of Participants With Overall Response
Overall response defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Per IMWG criteria, sCR: is defined as normal free light chain (FLC) ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5 % plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>= 90% reduction in serum M-protein plus urine M-protein level \< 100mg/24 hours; PR: \>= 50 % reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>= 90% or to \<200 mg/24 hours; if the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria.
Time frame: Up to 14.4 Months
Population: All treated analysis set included all participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daratumumab 8 mg/kg | Percentage of Participants With Overall Response | 11.1 percentage of participants |
| Daratumumab 16 mg/kg | Percentage of Participants With Overall Response | 29.2 percentage of participants |
Secondary
Duration of Response
Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in IMWG criteria. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component (the absolute increase must be \>=0.5 g/dL) and/or; urine M-component (the absolute increase must be \>=200 mg/24 hours) and/or; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be \>10 milligram per deciliter (mg/dL); Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.65 millimole per liter \[mmol/L\]) that can be attributed solely to the plasma cell proliferative disorder.
Time frame: Up to 14.4 Months
Population: Responders in all treated analysis set. Only those participants with confirmed PR and those who experienced progressive disease were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daratumumab 8 mg/kg | Duration of Response | NA months |
| Daratumumab 16 mg/kg | Duration of Response | 7.4 months |
Secondary
Overall Survival
Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method.
Time frame: Approximately up to 3 years
Population: All treated analysis set included all participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daratumumab 8 mg/kg | Overall Survival | 19.45 months |
| Daratumumab 16 mg/kg | Overall Survival | 18.60 months |
Secondary
Percentage of Participants With Clinical Benefit
Clinical benefit rate defined as percentage of participants who achieved minimal response (MR) or better. MR: \>=25% but \<= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%. If present at baseline 25% to 49% reduction in size of soft tissue plasmacytomas.
Time frame: Up to 14.4 Months
Population: All treated analysis set included all participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daratumumab 8 mg/kg | Percentage of Participants With Clinical Benefit | 22.2 percentage of participants |
| Daratumumab 16 mg/kg | Percentage of Participants With Clinical Benefit | 34.0 percentage of participants |
Secondary
Progression Free Survival
Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first.
Time frame: Up to 14.4 Months
Population: All treated analysis set included all participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daratumumab 8 mg/kg | Progression Free Survival | 4.86 months |
| Daratumumab 16 mg/kg | Progression Free Survival | 3.65 months |
Secondary
Time to Disease Progression
Time to progression was defined as the number of days from the date of first dose of daratumumab to the date of first record of disease progression.
Time frame: Up to 14.4 Months
Population: All treated analysis set included all participants who received at least 1 dose of daratumumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daratumumab 8 mg/kg | Time to Disease Progression | 4.86 months |
| Daratumumab 16 mg/kg | Time to Disease Progression | 3.71 months |
Secondary
Time to Response
Time to response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better).
Time frame: Up to 14.4 Months
Population: Responders in all treated analysis set. Only those participants with confirmed PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daratumumab 8 mg/kg | Time to Response | 0.99 months |
| Daratumumab 16 mg/kg | Time to Response | 0.99 months |