Relapsed/Refractory Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Aplidin, plitidepsin, dexamethasone
Brief summary
Study of Plitidepsin in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma.
Detailed description
Phase III Study in Patients with Relapsed/Refractory Multiple Myeloma to compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone measured by progression-free survival (PFS) and to evaluate tumor response, duration of response (DR), overall survival (OS) and to rule out any effect of plitidepsin on the duration of the QT/QTc interval (time corresponding to the beginning of depolarization to re-polarization of the ventricles).
Interventions
DRUGPlitidepsin
plitidepsin: powder and solvent for concentrate for solution for infusion. 2 mg vial + 4 ml ampoule. 5 mg/m2 intravenously (i.v.) over three hours on Day 1 and 15 every 4 weeks. dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks at least one hour before plitidepsin infusion.
DRUGDexamethasone
4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Sponsors
PharmaMar
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
* Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 * Life expectancy ≥ 3 months. * Patients previously diagnosed with multiple myeloma * Patients must have relapsed or relapsed and refractory multiple myeloma (MM) after at least three but not more than six prior therapeutic regimens for MM, including induction therapy and stem cell transplant in candidate patients, which will be considered as only one regimen. * Patients must have received previous bortezomib-containing and lenalidomide-containing regimens (or thalidomide where lenalidomide is not available) * Women must have a negative serum pregnancy test * Voluntarily signed and dated written informed consent
Exclusion criteria
* Concomitant diseases/conditions * Women who are pregnant or breast feeding. * Concomitant medications that include corticosteroids, chemotherapy, or other therapy that is or may be active against MM * Known hypersensitivity to any involved study drug or any of its formulation components
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Per Intention-to-treat (ITT) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Percentage of Participants With Progression Free Survival (PFS) as Per Intention-to-treat (ITT) at 6 Months | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months | To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization to the death due to any cause,assessed up to 5 years | Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact |
| Percentage of Participants With Overall Survival at 12 Months | From randomization to the death due to any cause,assessed up to 12 months | Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact |
| Percentage of Participants With Overall Survival at 24 Months | From randomization to the death due to any cause,assessed up to 24 months | Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact |
| Duration of Response (Independent Review Committee) | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Percentage of Participants With Duration of Response (Independent Review Committee) at 6 Months | From the date of first documentation of response to the date of disease progression or death, assessed up to 6 months | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Duration of Response (Investigator Assessment) | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Progression-free Survival (Investigator Assessment) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years | The secondary study analysis was based on Investigator's assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy. |
| Best Overall Response (Independent Review Committee) | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium \>11.5 mg/dL; NE, not evaluable |
| Overall Response Rate (Independent Review Committee) | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | Overall response rate including sCR, CR, VGPR, PR and MR. Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions |
| Overall Response Rate (Independent Review Committee) Excluding MR | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | Includes sCR, CR, VGPR and PR (excludes MR). Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas |
| Best Overall Response (Investigator Assessment) | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium \>11.5 mg/dL; NE, not evaluable |
| Overall Response Rate (Investigator Assessment) | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | Includes sCR, CR, VGPR, PR and MR. Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions |
| Overall Response Rate (Investigator Assessment) Excluding MR | From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years | Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas |
| Percentage of Participants With Duration of Response (Investigator Assessment) at 6 Months | From the date of first documentation of response to the date of disease progression or death, assessed up to 6 months | DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Percentage of Participants With Progression-free Survival (Investigator Assessment) at 6 Months | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months | The secondary study analysis was based on Investigator's assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy. |
Countries
Australia, Austria, Belgium, Czechia, France, Germany, Greece, Ireland, Italy, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
A total of 255 patients were enrolled. 171 Group A (Plitidepsin in combination with DXM) and 84 Group B (DXM alone). Enrolled patients between 29Jun10 and 19May15 (Last randomization). The first dose of the first patient was given on 19May15 and the last dose of the last patient was given on 07Aug17.
Participants by arm
| Arm | Count |
|---|---|
| Plitidepsin+Dexamethasone plitidepsin + dexamethasone combination
plitidepsin + dexamethasone: plitidepsin: powder and solvent for concentrate for solution for infusion. 2 mg vial + 4 ml ampoule. 5 mg/m2 intravenously (i.v.) over three hours on Day 1 and 15 every 4 weeks. dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks at least one hour before plitidepsin infusion. | 171 |
| Dexamethasone dexamethasone single agent
dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks. | 84 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Events (treatment-related) | 15 | 8 |
| Overall Study | Adverse Events (unrelated to | 9 | 1 |
| Overall Study | Death (due to adverse events | 0 | 1 |
| Overall Study | Death (non-related to the study | 19 | 8 |
| Overall Study | Patient Refusal | 24 | 12 |
| Overall Study | Physician Decision | 9 | 6 |
| Overall Study | Progressive Disease | 85 | 44 |
| Overall Study | Randomized but not treated | 4 | 1 |
Baseline characteristics
| Characteristic | Plitidepsin+Dexamethasone | Dexamethasone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 83 Participants | 48 Participants | 131 Participants |
| Age, Categorical Between 18 and 65 years | 88 Participants | 36 Participants | 124 Participants |
| Age, Continuous | 64 years | 65 years | 65 years |
| Beta-2 microglobulin | 4.1 mg/L | 4.2 mg/L | 4.1 mg/L |
| CrCL | 72.9 mL/min | 69.4 mL/min | 71.9 mL/min |
| Cytogenetic risk group at diagnosis High risk | 38 Participants | 16 Participants | 54 Participants |
| Cytogenetic risk group at diagnosis NA/ND/UK | 99 Participants | 47 Participants | 146 Participants |
| Cytogenetic risk group at diagnosis Standard risk | 34 Participants | 21 Participants | 55 Participants |
| Durie-Salmon stage at diagnosis Not Durie-Salmon stage at diagnosis | 1 Participants | 0 Participants | 1 Participants |
| Durie-Salmon stage at diagnosis Stage A | 0 Participants | 1 Participants | 1 Participants |
| Durie-Salmon stage at diagnosis Stage IA | 21 Participants | 9 Participants | 30 Participants |
| Durie-Salmon stage at diagnosis Stage IB | 0 Participants | 2 Participants | 2 Participants |
| Durie-Salmon stage at diagnosis Stage II | 3 Participants | 1 Participants | 4 Participants |
| Durie-Salmon stage at diagnosis Stage IIA | 44 Participants | 20 Participants | 64 Participants |
| Durie-Salmon stage at diagnosis Stage IIB | 1 Participants | 0 Participants | 1 Participants |
| Durie-Salmon stage at diagnosis Stage III | 2 Participants | 1 Participants | 3 Participants |
| Durie-Salmon stage at diagnosis Stage IIIA | 85 Participants | 43 Participants | 128 Participants |
| Durie-Salmon stage at diagnosis Stage IIIB | 14 Participants | 7 Participants | 21 Participants |
| ECOG PS PS 0 | 68 Participants | 31 Participants | 99 Participants |
| ECOG PS PS 1 | 74 Participants | 42 Participants | 116 Participants |
| ECOG PS PS 2 | 28 Participants | 11 Participants | 39 Participants |
| ECOG PS PS 3 | 1 Participants | 0 Participants | 1 Participants |
| Hb | 10.4 g/dL | 10.1 g/dL | 10.3 g/dL |
| International Staging System at diagnosis Not stage at diagnosis | 35 Participants | 18 Participants | 53 Participants |
| International Staging System at diagnosis Stage I | 72 Participants | 33 Participants | 105 Participants |
| International Staging System at diagnosis Stage II | 41 Participants | 18 Participants | 59 Participants |
| International Staging System at diagnosis Stage III | 23 Participants | 15 Participants | 38 Participants |
| MM type at diagnosis Non Secretory | 6 Participants | 1 Participants | 7 Participants |
| MM type at diagnosis Secretory IgA | 35 Participants | 21 Participants | 56 Participants |
| MM type at diagnosis Secretory IgD | 1 Participants | 1 Participants | 2 Participants |
| MM type at diagnosis Secretory IgG | 101 Participants | 51 Participants | 152 Participants |
| MM type at diagnosis Secretory IgM | 1 Participants | 0 Participants | 1 Participants |
| MM type at diagnosis Secretory Light chain disease | 27 Participants | 10 Participants | 37 Participants |
| Number of lines of prior systemic therapy | 4 lines | 4 lines | 4 lines |
| Platelets | 140 platelets*10^9/L | 154 platelets*10^9/L | 144 platelets*10^9/L |
| Prior radiotherapy No | 103 Participants | 49 Participants | 152 Participants |
| Prior radiotherapy Yes | 68 Participants | 35 Participants | 103 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Austria | 21 Participants | 7 Participants | 28 Participants |
| Region of Enrollment Czechia | 23 Participants | 10 Participants | 33 Participants |
| Region of Enrollment Greece | 12 Participants | 7 Participants | 19 Participants |
| Region of Enrollment Netherlands | 5 Participants | 4 Participants | 9 Participants |
| Region of Enrollment New Zealand | 7 Participants | 1 Participants | 8 Participants |
| Region of Enrollment Portugal | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment South Korea | 8 Participants | 4 Participants | 12 Participants |
| Region of Enrollment Spain | 13 Participants | 7 Participants | 20 Participants |
| Region of Enrollment United Kingdom | 12 Participants | 6 Participants | 18 Participants |
| Region of Enrollment United States | 6 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Female | 74 Participants | 49 Participants | 123 Participants |
| Sex: Female, Male Male | 97 Participants | 35 Participants | 132 Participants |
| Time from first diagnosis to randomization | 71.8 months | 70 months | 71.3 months |
| Time from last PD/relapse to first study dose | 6.1 weeks | 6.4 weeks | 6.2 weeks |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 126 / 167 | 74 / 83 |
| other Total, other adverse events | 161 / 167 | 80 / 83 |
| serious Total, serious adverse events | 99 / 167 | 26 / 83 |
Outcome results
Primary
Percentage of Participants With Progression Free Survival (PFS) as Per Intention-to-treat (ITT) at 6 Months
To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Percentage of Participants With Progression Free Survival (PFS) as Per Intention-to-treat (ITT) at 6 Months | 20.0 percentage of participants |
| Dexamethasone | Percentage of Participants With Progression Free Survival (PFS) as Per Intention-to-treat (ITT) at 6 Months | 10.0 percentage of participants |
p-value: 0.0618Normal approximation
Primary
Progression Free Survival (PFS) as Per Intention-to-treat (ITT)
To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin+Dexamethasone | Progression Free Survival (PFS) as Per Intention-to-treat (ITT) | 2.6 months |
| Dexamethasone | Progression Free Survival (PFS) as Per Intention-to-treat (ITT) | 1.7 months |
p-value: =0.005495% CI: [0.447, 0.885]Log Rank
Secondary
Best Overall Response (Independent Review Committee)
Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium \>11.5 mg/dL; NE, not evaluable
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plitidepsin+Dexamethasone | Best Overall Response (Independent Review Committee) | VGR | 2 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Independent Review Committee) | PR | 15 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Independent Review Committee) | MR | 22 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Independent Review Committee) | SD | 43 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Independent Review Committee) | PD | 41 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Independent Review Committee) | NE | 48 Participants |
| Dexamethasone | Best Overall Response (Independent Review Committee) | PD | 35 Participants |
| Dexamethasone | Best Overall Response (Independent Review Committee) | VGR | 0 Participants |
| Dexamethasone | Best Overall Response (Independent Review Committee) | SD | 21 Participants |
| Dexamethasone | Best Overall Response (Independent Review Committee) | PR | 1 Participants |
| Dexamethasone | Best Overall Response (Independent Review Committee) | NE | 25 Participants |
| Dexamethasone | Best Overall Response (Independent Review Committee) | MR | 2 Participants |
Secondary
Best Overall Response (Investigator Assessment)
Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium \>11.5 mg/dL; NE, not evaluable
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Plitidepsin+Dexamethasone | Best Overall Response (Investigator Assessment) | SD | 61 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Investigator Assessment) | PR | 16 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Investigator Assessment) | PD | 37 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Investigator Assessment) | MR | 31 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Investigator Assessment) | NE | 22 Participants |
| Plitidepsin+Dexamethasone | Best Overall Response (Investigator Assessment) | VGPR | 4 Participants |
| Dexamethasone | Best Overall Response (Investigator Assessment) | NE | 13 Participants |
| Dexamethasone | Best Overall Response (Investigator Assessment) | VGPR | 0 Participants |
| Dexamethasone | Best Overall Response (Investigator Assessment) | MR | 0 Participants |
| Dexamethasone | Best Overall Response (Investigator Assessment) | SD | 31 Participants |
| Dexamethasone | Best Overall Response (Investigator Assessment) | PD | 39 Participants |
| Dexamethasone | Best Overall Response (Investigator Assessment) | PR | 1 Participants |
Secondary
Duration of Response (Independent Review Committee)
DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
Population: Patients with documentation of response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin+Dexamethasone | Duration of Response (Independent Review Committee) | 3.7 months |
| Dexamethasone | Duration of Response (Independent Review Committee) | 1.8 months |
p-value: =0.101595% CI: [0.113, 1.303]Log Rank
Secondary
Duration of Response (Investigator Assessment)
DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
Population: Patients with documentation of response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin+Dexamethasone | Duration of Response (Investigator Assessment) | 5.1 months |
| Dexamethasone | Duration of Response (Investigator Assessment) | 0.9 months |
Comparison: Pre-specifiedp-value: =0.000195% CI: [0.004, 0.479]Log Rank
Secondary
Overall Response Rate (Independent Review Committee)
Overall response rate including sCR, CR, VGPR, PR and MR. Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Overall Response Rate (Independent Review Committee) | 22.8 percentage of participants |
| Dexamethasone | Overall Response Rate (Independent Review Committee) | 3.6 percentage of participants |
p-value: <0.0001Fisher Exact
Secondary
Overall Response Rate (Independent Review Committee) Excluding MR
Includes sCR, CR, VGPR and PR (excludes MR). Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Overall Response Rate (Independent Review Committee) Excluding MR | 9.9 percentage of participants |
| Dexamethasone | Overall Response Rate (Independent Review Committee) Excluding MR | 1.2 percentage of participants |
p-value: 0.0085Fisher Exact
Secondary
Overall Response Rate (Investigator Assessment)
Includes sCR, CR, VGPR, PR and MR. Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Overall Response Rate (Investigator Assessment) | 29.8 percentage of participants |
| Dexamethasone | Overall Response Rate (Investigator Assessment) | 1.2 percentage of participants |
p-value: <0.0001Fisher Exact
Secondary
Overall Response Rate (Investigator Assessment) Excluding MR
Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Overall Response Rate (Investigator Assessment) Excluding MR | 11.7 percentage of participants |
| Dexamethasone | Overall Response Rate (Investigator Assessment) Excluding MR | 1.2 percentage of participants |
p-value: 0.0029Fisher Exact
Secondary
Overall Survival
Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact
Time frame: From randomization to the death due to any cause,assessed up to 5 years
Population: All Randomized Patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin+Dexamethasone | Overall Survival | 11.6 months |
| Dexamethasone | Overall Survival | 8.9 months |
Comparison: Pre-specifiedp-value: =0.126195% CI: [0.596, 1.067]Log Rank
Secondary
Percentage of Participants With Duration of Response (Independent Review Committee) at 6 Months
DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 6 months
Population: Patients with documentation of response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Percentage of Participants With Duration of Response (Independent Review Committee) at 6 Months | 41.2 percentage of participants |
| Dexamethasone | Percentage of Participants With Duration of Response (Independent Review Committee) at 6 Months | 0.0 percentage of participants |
Secondary
Percentage of Participants With Duration of Response (Investigator Assessment) at 6 Months
DR was calculated from the date of first documentation of response to the date of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From the date of first documentation of response to the date of disease progression or death, assessed up to 6 months
Population: Patients with documentation of response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Percentage of Participants With Duration of Response (Investigator Assessment) at 6 Months | 38.2 percentage of participants |
| Dexamethasone | Percentage of Participants With Duration of Response (Investigator Assessment) at 6 Months | 0.0 percentage of participants |
Secondary
Percentage of Participants With Overall Survival at 12 Months
Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact
Time frame: From randomization to the death due to any cause,assessed up to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Percentage of Participants With Overall Survival at 12 Months | 48.3 percentage of participants |
| Dexamethasone | Percentage of Participants With Overall Survival at 12 Months | 42.1 percentage of participants |
p-value: 0.3625Normal approximation
Secondary
Percentage of Participants With Overall Survival at 24 Months
Overall Survival (OS) is defined as the time from the date of randomization to the date of death or last contact
Time frame: From randomization to the death due to any cause,assessed up to 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Percentage of Participants With Overall Survival at 24 Months | 30.8 percentage of participants |
| Dexamethasone | Percentage of Participants With Overall Survival at 24 Months | 21.0 percentage of participants |
p-value: 0.1037Normal approximation
Secondary
Percentage of Participants With Progression-free Survival (Investigator Assessment) at 6 Months
The secondary study analysis was based on Investigator's assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plitidepsin+Dexamethasone | Percentage of Participants With Progression-free Survival (Investigator Assessment) at 6 Months | 26.4 percentage of participants |
| Dexamethasone | Percentage of Participants With Progression-free Survival (Investigator Assessment) at 6 Months | 8.1 percentage of participants |
p-value: 0.0002Normal approximation
Secondary
Progression-free Survival (Investigator Assessment)
The secondary study analysis was based on Investigator's assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
Population: All Randomized Patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Plitidepsin+Dexamethasone | Progression-free Survival (Investigator Assessment) | 2.9 months |
| Dexamethasone | Progression-free Survival (Investigator Assessment) | 1.1 months |
p-value: <0.000195% CI: [0.382, 0.686]Log Rank