A Phase 3 interventional study of Dexamethasone and Bortezomib in Multiple Myeloma, sponsored by Janssen-Cilag G.m.b.H. Completed at 40 sites in Germany. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-08-15.
Sponsored by Janssen-Cilag G.m.b.H · Phase 3, Interventional, and Treatment
The purpose of this study is to compare bortezomib, dexamethasone and cyclophosphamide to bortezomib and dexamethasone alone for primary refractory or relapsed multiple myeloma.
This is a prospective, multi-centre, randomized (the study drug is assigned by chance), controlled, open-label (all people involved in the study know the identity of the assigned drug), parallel (each group of patients will be treated at the same time) group phase III study to determine the efficacy of the standard therapy of bortezomib and low dose dexamethasone in combination with or without continuous low dose oral cyclophosphamide for primary refractory or relapsed myeloma patients (1st - 3rd relapse). The study will consist of screening period, which may last from day -14 until day -1 before application of the first dose of bortezomib (on cycle 1, day 1), treatment phase begins on cycle 1 day 1 and continues until completion or discontinuation of all study drugs and follow-up phase. All patients will be followed up after end of treatment regardless of their response. Eligible patients will be randomized in 1:1 ratio to receive either treatment arms (Group A: receiving bortezomib plus dexamethasone or Group B receiving bortezomib plus dexamethasone plus cyclophosphamide). Patients will receive up to eight 3-weeks treatment cycles, unless they experience either unacceptable toxicity or if the patients request to withdraw from the study. The maximum number of cycles is dependent on patient response and investigator's discretion. It is recommended that patients with a confirmed complete response (CR) receive 2 additional cycles beyond a confirmation. Patients who do not achieve a CR but a partial response will receive a total of 8 cycles. For patients achieving stable disease it is within the investigator's discretion to continue study treatment beyond 6 cycles, after discussion with the sponsor. After completion of treatment the patients will be followed up every 12 weeks for up to 72 weeks. If the study is still ongoing a further follow up period will be done every 26 weeks until study end, or until the patient reaches progressive disease or start of alternative anti-myeloma therapy, if earlier. In case progressive disease (PD) has already been established during the treatment phase the patients will not enter the follow-up phase. In case of PD or start of alternative anti-myeloma treatment before the end of study the follow-up phase will be discontinued for the patient but the date of death of the patient will be documented (if applicable) before the end of study.
3,632 studies on the registry are indexed under Multiple Myeloma; 745 are open to participants now.
This study's enrollment of 96 is above the median of 41 across 2,907 interventional studies indexed under Multiple Myeloma.
Browse Multiple Myeloma studies →Janssen-Cilag G.m.b.H is the lead sponsor of 11 studies on the registry; 1 is open to participants now.
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Exclusion Criteria:
Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.
Drug: Dexamethasone · Drug: Bortezomib
Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Drug: Dexamethasone · Drug: Bortezomib · Drug: Cyclophosphamide
Type=exact number, number=20, unit=mg, form=tablet, route=oral. The patients will receive 20 mg of dexamethasone on days 1+2,4+5,8+9,11+12 for 21 days for 8 cycles.
Type=exact number, number=1.3, unit=mg, form=injection, route=intravenous. The patients will receive 1.3mg/m2 on days 1,4,8,11 for 21 days for 8 cycles.
Type=exact number, number=50, unit=mg, form=tablet, route=oral. The patients will receive 50 mg of cyclophosphamide once daily continuously from cycle 1 to 8.
Time to Progression of Disease
'Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of \>=25% from lowest level in Serum M-component or (the absolute increase must be \>=0.5 gram per deciliter \[g/dL\]); Urine M component or (the absolute increase must be \>=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase \>10 mg/dL. Bone marrow plasma cell percentage \>=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.
Time frame: From the date of randomization until the disease progression or participant's death from any cause whichever occurred first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication)
Progression-Free Survival (PFS)
PFS is defined as time from randomization to myeloma progression according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of ≥25 percent from lowest response level in Serum M-component and/or (the absolute increase must be ≥0.5 g/dL) Urine M-component and/or (the absolute increase must be ≥200 mg/24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be \>10 mg/dL. Bone marrow plasma cell percentage: the absolute percent must be ≥10 percent. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.65mmol/L) that can be attributed solely to the plasma cell proliferative disorder. PFS included disease progression as well as death.
Time frame: From the date of randomization until the disease progression or participant's death from any cause whichever occured first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication)
Overall Survival (OS)
Time interval in months time from randomisation to death from any cause.
Time frame: From the date of randomization until Month 49
Overall Response Rate (ORR) - International Myeloma Working Group (IMWG) Response Criteria
Percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) is reported in the below table. IMWG criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescencec; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hour.
Time frame: Up to 46 days after last bortezomib dose, or as soon as possible after early discontinuation of study treatment or before start of alternative anti-myeloma therapy
The study was conducted between 23 December 2008 and 10 January 2013 and recruited patients from 42 study centers in Germany.
| Milestone | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| Started | 46 | 47 |
| Intent-to-treat participants | 43 | 47 |
| Completed | 14 | 15 |
| Not completed | 32 | 32 |
| Withdrew: Adverse event | 16 | 15 |
| Withdrew: Death | 2 | 0 |
| Withdrew: Progressive disease | 1 | 0 |
| Withdrew: Complete response | 0 | 1 |
| Withdrew: Stable disease | 1 | 2 |
| Withdrew: Protocol violation | 3 | 4 |
| Withdrew: Withdrawal by subject | 5 | 3 |
| Withdrew: Non compliance | 0 | 1 |
| Withdrew: Reason not specified | 3 | 4 |
| Withdrew: Data not available | 1 | 2 |
| Milestone | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| Started | 26 | 31 |
| Completed | 2 | 0 |
| Not completed | 24 | 31 |
| Withdrew: Death | 0 | 4 |
| Withdrew: Other | 0 | 3 |
| Withdrew: Lost to follow-up | 2 | 0 |
| Withdrew: Progression/relapse | 22 | 24 |
'Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of \>=25% from lowest level in Serum M-component or (the absolute increase must be \>=0.5 gram per deciliter \[g/dL\]); Urine M component or (the absolute increase must be \>=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase \>10 mg/dL. Bone marrow plasma cell percentage \>=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.
| Months | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| Time to Progression of Disease | 12.6 (9.83 to 14.43) | 9.9 (8.60 to 11.40) |
PFS is defined as time from randomization to myeloma progression according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of ≥25 percent from lowest response level in Serum M-component and/or (the absolute increase must be ≥0.5 g/dL) Urine M-component and/or (the absolute increase must be ≥200 mg/24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be \>10 mg/dL. Bone marrow plasma cell percentage: the absolute percent must be ≥10 percent. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.65mmol/L) that can be attributed solely to the plasma cell proliferative disorder. PFS included disease progression as well as death.
| Months | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| Progression-Free Survival (PFS) | 12.6 (9.83 to 14.43) | 9.9 (8.60 to 11.40) |
Time interval in months time from randomisation to death from any cause.
| Months | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| Overall Survival (OS) | NA (NA to NA) | 41.50 (24.87 to NA) |
Percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) is reported in the below table. IMWG criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescencec; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hour.
| Percentage of participants | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| Overall Response Rate (ORR) - International Myeloma Working Group (IMWG) Response Criteria | 74.4 (NA to NA) | 70.2 |
Collected over Approximately 5 years. Non-serious events are listed at a 2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Vd (Bortezomib + Dexamethasone) | — | 15/46 (32.6%) | 43/46 (93.5%) |
| Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) | — | 14/47 (29.8%) | 46/47 (97.9%) |
| Event | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| PneumoniaInfections and infestations | 4/46 | 4/47 |
| Multiple myelomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 3/46 | 0/47 |
| DiverticulitisInfections and infestations | 2/46 | 0/47 |
| SepsisInfections and infestations | 2/46 | 0/47 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 2/46 | 1/47 |
| SyncopeNervous system disorders | 0/46 | 2/47 |
| InfectionInfections and infestations | 1/46 | 0/47 |
| ConstipationGastrointestinal disorders | 1/46 | 1/47 |
| Ileus paralyticGastrointestinal disorders | 1/46 | 0/47 |
| Inguinal hernia, obstructiveGastrointestinal disorders | 1/46 | 0/47 |
| Event | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) |
|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 17/46 | 18/47 |
| FatigueGeneral disorders | 13/46 | 18/47 |
| DiarrhoeaGastrointestinal disorders | 11/46 | 17/47 |
| ConstipationGastrointestinal disorders | 10/46 | 13/47 |
| AnaemiaBlood and lymphatic system disorders | 12/46 | 6/47 |
| NauseaGastrointestinal disorders | 7/46 | 11/47 |
| NasopharyngitisInfections and infestations | 3/46 | 11/47 |
| Oedema peripheralGeneral disorders | 7/46 | 10/47 |
| PolyneuropathyNervous system disorders | 7/46 | 9/47 |
| Peripheral sensory neuropathyNervous system disorders | 3/46 | 9/47 |
Number of Intent-to-treat (ITT) participants were included in Baseline analysis. Out of 93 randomized participants (Vd=46; Vcd=47), follow-up data on treatment response was not available for 3 participants, so, they were excluded from the Intent-to-treat (ITT) analysis data set and so, ITT included 90 participants (Vd=43; Vcd=47).
| Age, Continuous(Years) | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) | Total |
|---|---|---|---|
| Mean | 68 ± 10 | 71 ± 7 | 69 ± 9 |
| Sex: Female, Male(Participants) | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) | Total |
|---|---|---|---|
| Female | 18 | 21 | 39 |
| Male | 25 | 26 | 51 |
| Race/Ethnicity, Customized(Participants) | Vd (Bortezomib + Dexamethasone) | Vcd (Bortezomib + Low-dose Dexamethasone + Cyclophosphamide) | Total |
|---|---|---|---|
| Caucasian | 42 | 47 | 89 |
| African | 1 | 0 | 1 |
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Janssen-Cilag G.m.b.H