Multiple Myeloma
Conditions
Keywords
Untreated Multiple Myeloma, daratumumab
Brief summary
The purpose of this study is to evaluate if the addition of daratumumab to Bortezomib, Thalidomide and Dexamethasone will increase the stringent complete response rate after consolidation therapy and increase the progression free survival after daratumumab maintenance therapy in transplant eligible participants with previously untreated Multiple Myeloma.
Detailed description
This is a randomized, open-label (identity of assigned treatment will be known to participants and study staff), 2-arm (2 treatment groups), multicenter study of daratumumab in participants diagnosed with previously untreated Multiple Myeloma who are eligible for high dose chemotherapy and autologous stem cell transplantation (transplantation of own bone marrow). Participants will be randomized (assigned by chance) to one of 2 treatment groups to either receive daratumumab plus bortezomib, thalidomide and dexamethasone or bortezomib, thalidomide and dexamethasone for induction (before transplantation) and consolidation (after transplantation) treatment. All responders will then be re-randomized (assigned by chance) to one of 2 treatment groups to receive maintenance treatment with daratumumab only or observation (no treatment). The study will include a 28-Day Screening Phase, a Treatment Phase of 6 treatment cycles (each cycle is 4 weeks in duration for total period of 30 weeks), and a Follow up Phase of 2 years. The total duration for each participant in the study will be approximately 138 weeks. The end of the study will occur approximately 5 years after the last participant is randomized in the second phase of the study. Disease assessments will be performed every 4 weeks in the first phase of the study and then every 8 weeks in the second phase of the study. Safety will be monitored throughout the study.
Interventions
DRUGBortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD)
Part 1: 4 Cycles of Bortezomib,Thalidomide and Dexamethasone induction therapy, followed by Autologous Stem Cell Transplantation, followed by 2 cycles of Bortezomib, Thalidomide and Dexamethasone consolidation
DRUGBortezomib, Thalidomide, Dexamethasone (VTD) + daratumumab
Part 1: 4 Cycles of Bortezomib, Thalidomide and Dexamethasone plus daratumumab 16mg/kg induction therapy, followed by Autologous Stem Cell Transplantation, followed by 2 cycles of Bortezomib, Thalidomide and Dexamethasone plus daratumumab 16 mg/kg consolidation
DRUGDaratumumab
Daratumumab 16mg/kg every 8 weeks for 2 years
Sponsors
HOVON - Dutch Haemato-Oncology Association
Janssen Research & Development, LLC
Intergroupe Francophone du Myelome
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of previously untreated multiple myeloma (MM) * Have a confirmed diagnosis and eligible for high dose chemotherapy and autologous stem cell transplantation, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0,1 or 2
Exclusion criteria
* previous treatment for Multiple Myeloma * Primary amyloidosis, Plasma Cell Leukemia or Smoldering Multiple Myeloma * Prior or concurrent exposure to systemic therapy or SCT (Stem Cell Transplantation) for any plasma cell dyscrasia, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment, or received an investigational drug or used an invasive investigational medical device within 4 weeks before Cycle 1, Day 1 * history of malignancy (other than Multiple Myeloma) within 10 years before the date of randomization, except for the following if treated and not active: basal cell or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of breast, or International Federation of Gynecology and Obstetrics (FIGO) Stage 1 carcinoma of the cervix * known chronic obstructive pulmonary disease (COPD) or moderate to severe asthma * any concurrent medical or psychiatric condition or disease (eg, autoimmune disease, active systemic disease, myelodysplasia) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-Consolidation Stringent Complete Response (sCR) Rate | At day 100 post Autologous Stem Cell Transplant (ASCT), up to 114 days post ASCT | Post-consolidation sCR rate is defined as the percentage of ITT subjects who achieved or maintained sCR status within 30 days of Day 100 post Autologous Stem Cell Transplant (ASCT). The sCR status is assessed using the computerized algorithm according to IMWG response criteria, and must be achieved on or prior to start of subsequent therapies. Subjects must not die or progress by Day 100 post ASCT. According to the IMWG consensus recommendations for multiple myeloma treatment response criteria from 2006, the stringent complete response (sCR) was defined by a negative immunofixation on the serum and urine, and a disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow, plus normal free-light chain ratio and the absence of clonal bone marrow plasma cells by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. |
| Progression Free Survival (PFS) Post Completion of Maintenance Therapy | From the date of second randomization to either progressive disease or death which ever occurred first, with a median follow-up time of 35.4 months (cut-off for analysis was 26 months after the last rando 2 date). | Progression Free Survival (PFS) post completion of maintenance therapy is defined as the duration from the date of second randomization to either progressive disease (according to the IMWG criteria specified in the protocol), or death, whichever occurs first (=all these considered as events) at the completion of Maintenance therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) From First Randomization up to the End of the Study | From the date of first randomization to either progressive disease or death which ever occurred first, with a median follow-up time of 80.1 months at the end of the study | Progression Free Survival (PFS) is defined as the duration from the date of first randomization to either progressive disease (according to the IMWG criteria specified in the protocol), or death, whichever occurs first (=all these considered as events) at the end of the study |
Countries
Belgium, France, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VTd Only Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD), not re-randomized in maintenance phase | 114 |
| DVTd Only Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD), not re-randomized in maintenance phase | 85 |
| VTd-OBS Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) re-randomized to observation | 215 |
| VTd-DARA Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) re-randomized to daratumumab monotherapy | 213 |
| DVTd-OBS Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) re-randomized to observation | 229 |
| DVTd-DARA Daratumumab in combination with Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) re-randomized to daratumumab monotherapy | 229 |
| Total | 1,085 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Consent withdrawn | 5 | 6 | 1 | 1 | 0 | 0 |
| Overall Study | Death | 50 | 37 | 48 | 41 | 21 | 25 |
| Overall Study | Lost to Follow-up | 5 | 3 | 1 | 1 | 3 | 0 |
| Overall Study | Sponsor's decision | 1 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | VTd Only | DVTd Only | VTd-OBS | VTd-DARA | DVTd-OBS | DVTd-DARA | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 6.36 | 57.8 years STANDARD_DEVIATION 7.5 | 56 years STANDARD_DEVIATION 6.96 | 56.3 years STANDARD_DEVIATION 7.38 | 56.8 years STANDARD_DEVIATION 6.83 | 56.4 years STANDARD_DEVIATION 6.79 | 56.6 years STANDARD_DEVIATION 6.98 |
| Baseline ISS Stage I | 47 participants | 25 participants | 88 participants | 93 participants | 83 participants | 96 participants | 432 participants |
| Baseline ISS Stage II | 52 participants | 41 participants | 96 participants | 85 participants | 118 participants | 96 participants | 488 participants |
| Baseline ISS Stage III | 15 participants | 19 participants | 31 participants | 35 participants | 28 participants | 37 participants | 165 participants |
| Baseline Type of Myeloma Biclonal | 1 participants | 2 participants | 10 participants | 8 participants | 5 participants | 5 participants | 31 participants |
| Baseline Type of Myeloma IgA | 15 participants | 14 participants | 46 participants | 43 participants | 36 participants | 37 participants | 191 participants |
| Baseline Type of Myeloma IgD | 3 participants | 1 participants | 3 participants | 7 participants | 2 participants | 2 participants | 18 participants |
| Baseline Type of Myeloma IgG | 79 participants | 54 participants | 126 participants | 128 participants | 159 participants | 138 participants | 684 participants |
| Baseline Type of Myeloma IgM | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 1 participants | 3 participants |
| Baseline Type of Myeloma Kappa | 11 participants | 9 participants | 17 participants | 18 participants | 17 participants | 27 participants | 99 participants |
| Baseline Type of Myeloma Lambda | 3 participants | 5 participants | 10 participants | 7 participants | 8 participants | 17 participants | 50 participants |
| Baseline Type of Myeloma Negative immunofixation | 2 participants | 0 participants | 2 participants | 1 participants | 2 participants | 2 participants | 9 participants |
| Bone marrow cellularity Hypercellular | 30 participants | 28 participants | 62 participants | 63 participants | 62 participants | 46 participants | 291 participants |
| Bone marrow cellularity Indeterminate | 1 participants | 3 participants | 8 participants | 8 participants | 6 participants | 8 participants | 34 participants |
| Bone marrow cellularity Missing | 2 participants | 1 participants | 4 participants | 2 participants | 5 participants | 6 participants | 20 participants |
| Bone marrow cellularity Moderately cellular | 24 participants | 19 participants | 50 participants | 42 participants | 41 participants | 47 participants | 223 participants |
| Bone marrow cellularity Normocellular | 52 participants | 31 participants | 78 participants | 93 participants | 101 participants | 112 participants | 467 participants |
| Bone marrow cellularity Severely acellular | 5 participants | 3 participants | 13 participants | 5 participants | 14 participants | 10 participants | 50 participants |
| Presence of diffuse myeloma-related osteopenia Missing | 0 participants | 0 participants | 0 participants | 2 participants | 1 participants | 2 participants | 5 participants |
| Presence of diffuse myeloma-related osteopenia No | 100 participants | 76 participants | 197 participants | 194 participants | 203 participants | 208 participants | 978 participants |
| Presence of diffuse myeloma-related osteopenia Yes | 14 participants | 9 participants | 18 participants | 17 participants | 25 participants | 19 participants | 102 participants |
| Presence of evaluable bone marrow assessment No | 3 participants | 0 participants | 3 participants | 3 participants | 4 participants | 6 participants | 19 participants |
| Presence of evaluable bone marrow assessment Yes | 111 participants | 85 participants | 212 participants | 210 participants | 225 participants | 223 participants | 1066 participants |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment BELGIUM | 15 participants | 5 participants | 11 participants | 18 participants | 23 participants | 17 participants | 89 participants |
| Region of Enrollment FRANCE | 70 participants | 64 participants | 191 participants | 169 participants | 177 participants | 183 participants | 854 participants |
| Region of Enrollment NETHERLANDS | 29 participants | 16 participants | 13 participants | 26 participants | 29 participants | 29 participants | 142 participants |
| Sex: Female, Male Female | 42 Participants | 37 Participants | 94 Participants | 87 Participants | 96 Participants | 94 Participants | 450 Participants |
| Sex: Female, Male Male | 72 Participants | 48 Participants | 121 Participants | 126 Participants | 133 Participants | 135 Participants | 635 Participants |
| Time since initial diagnosis to randomization (months) | 1.6 months STANDARD_DEVIATION 2.65 | 1.3 months STANDARD_DEVIATION 0.96 | 1.2 months STANDARD_DEVIATION 0.86 | 1.2 months STANDARD_DEVIATION 0.87 | 1.2 months STANDARD_DEVIATION 1.08 | 1.2 months STANDARD_DEVIATION 0.95 | 1.2 months STANDARD_DEVIATION 1.25 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 139 / 542 | 83 / 543 | 48 / 215 | 41 / 211 | 21 / 229 | 25 / 229 |
| other Total, other adverse events | 529 / 538 | 534 / 536 | 170 / 215 | 194 / 211 | 198 / 229 | 205 / 229 |
| serious Total, serious adverse events | 261 / 538 | 264 / 536 | 35 / 215 | 58 / 211 | 50 / 229 | 43 / 229 |
Outcome results
Primary
Post-Consolidation Stringent Complete Response (sCR) Rate
Post-consolidation sCR rate is defined as the percentage of ITT subjects who achieved or maintained sCR status within 30 days of Day 100 post Autologous Stem Cell Transplant (ASCT). The sCR status is assessed using the computerized algorithm according to IMWG response criteria, and must be achieved on or prior to start of subsequent therapies. Subjects must not die or progress by Day 100 post ASCT. According to the IMWG consensus recommendations for multiple myeloma treatment response criteria from 2006, the stringent complete response (sCR) was defined by a negative immunofixation on the serum and urine, and a disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow, plus normal free-light chain ratio and the absence of clonal bone marrow plasma cells by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
Time frame: At day 100 post Autologous Stem Cell Transplant (ASCT), up to 114 days post ASCT
Population: All participants randomized in the first randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Part 1 | Post-Consolidation Stringent Complete Response (sCR) Rate | 110 Participants |
| Arm B Part 1 | Post-Consolidation Stringent Complete Response (sCR) Rate | 157 Participants |
p-value: 0.00195% CI: [1.21, 2.12]Cochran-Mantel-Haenszel
Primary
Progression Free Survival (PFS) Post Completion of Maintenance Therapy
Progression Free Survival (PFS) post completion of maintenance therapy is defined as the duration from the date of second randomization to either progressive disease (according to the IMWG criteria specified in the protocol), or death, whichever occurs first (=all these considered as events) at the completion of Maintenance therapy.
Time frame: From the date of second randomization to either progressive disease or death which ever occurred first, with a median follow-up time of 35.4 months (cut-off for analysis was 26 months after the last rando 2 date).
Population: All participants randomized in the second randomization even if they did not receive any study treatment dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A Part 1 | Progression Free Survival (PFS) Post Completion of Maintenance Therapy | 46.7 Months |
| Arm B Part 1 | Progression Free Survival (PFS) Post Completion of Maintenance Therapy | NA Months |
p-value: <0.000195% CI: [0.42, 0.68]Log Rank
Secondary
Progression Free Survival (PFS) From First Randomization up to the End of the Study
Progression Free Survival (PFS) is defined as the duration from the date of first randomization to either progressive disease (according to the IMWG criteria specified in the protocol), or death, whichever occurs first (=all these considered as events) at the end of the study
Time frame: From the date of first randomization to either progressive disease or death which ever occurred first, with a median follow-up time of 80.1 months at the end of the study
Population: All participants randomized in the first randomization even if they did not receive any study treatment dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A Part 1 | Progression Free Survival (PFS) From First Randomization up to the End of the Study | 52.8 Months |
| Arm B Part 1 | Progression Free Survival (PFS) From First Randomization up to the End of the Study | 83.7 Months |
p-value: <0.000195% CI: [0.52, 0.72]Log Rank