Multiple Myeloma
Conditions
Keywords
multiple myeloma, plitidepsin, APLIDIN
Brief summary
Study of Plitidepsin (Aplidin®) to determine the recommended dose (RD) of plitidepsin in Combination with Bortezomib and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma.
Detailed description
Phase I Multicenter, Open-label, Dose-escalating Clinical and Pharmacokinetic Trial of Plitidepsin (Aplidin®) to determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM), to determine the efficacy of the combination plitidepsin/bortezomib/dexamethasone, to evaluate the safety and tolerability of the combination in patients with relapsing and/or refractory MM and to study the pharmacokinetics (PK) and pharmacodynamics (PDy) of plitidepsin in combination with bortezomib and dexamethasone.
Interventions
Sponsors
PharmaMar
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years. * Prior autologous transplantation (HSCT) patients are allowed. * Patients must have received at least one previous treatment line of induction, chemotherapy, chemotherapy and transplantation or previous treatment with bortezomib or another proteasome drug
Exclusion criteria
* Previous treatment with plitidepsin. * Active or metastatic primary malignancy other than MM. * Serious concomitant systemic disorders * History of hypersensitivity reactions to bortezomib, polyoxyl 35 castor oil or mannitol * Neuropathy * Pregnant and/or lactating women * HIV infection * Active hepatitis B or C virus infection. * Treatment with any Investigational Medicinal Product (IMP) in the 30 days before inclusion in the study * Plasma cell leukemia at the time of study entry * Contraindication for the use of steroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dose of Plitidepsin in Combination With Bortezomib and Dexamethasone | After 28-day cycle | To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle. |
| Recommended Dose of Bortezomib in Combination With Plitidepsin and Dexamethasone | After 28-day cycle | To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle. |
| Recommended Dose of Dexamethasone in Combination With Plitidepsin and Bortezomib | After 28-day cycle | To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle. |
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | After 28-day cycle | DLTs were defined as: Hematological Toxicity * Grade 3/4 neutropenia associated with fever or lasting\>7 days related to the study treatment * Grade 3/4 thrombocytopenia accompanied by grade 3/4 hemorrhage * Extensive bone marrow (BM) infiltration, DLT was defined as grade 4 thrombocytopenia with grade 3/4 hemorrhage or grade 4 neutropenia lasting \>7 days or with fever Non-hematological Toxicity * Grade 3/4 nausea and vomiting refractory to antiemetic therapy * Grade≥3 muscular Adverse events (AE) (myalgia, muscular weakness, muscle cramps, myopathy) * Grade≥3 alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) lasting more than 1 week * Grade≥3 bilirubin increase * Grade≥3 creatine phosphokinase (CPK) increase * Cardiac toxicity * Symptomatic or treatment-requiring grade ≥1 cardiac arrhythmia related to plitidepsin * Grade≥1 left ventricular systolic dysfunction related to plitidepsin * Neuropathic pain and peripheral sensory neuropathy related to BTZ |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression Rates | From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years | Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD. |
| Progression-free Survival | from the date of the first infusion to the date of documented PD or death, up to 4 years | Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first |
| Response According to International Myeloma Working Group Criteria | Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years | Stringent complete response (sCR) normal Free Light Chains (FLC) ratio. No clonal cells Complete response (CR) no serum/urine M-protein, no evidence of soft tissue plasmacytoma. \<5% clonal plasma cells 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 |
| Event-free Survival | From the date of first infusion to the date of documented PD or death, up to 4 years | Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance |
| Event-free Survival Rates | from the date of first infusion to the date of documented PD or death, up to 4 years | Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance |
| Progression-free Survival Rates | From the date of the first infusion to the date of documented PD or death, up to 4 years | Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first |
| Overall Response Rate | Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years | Overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR) according to the International Myeloma Working Group (IMWG) criteria |
| Duration of Response | From the date of the first documentation of response to the date of PD or further therapy or death, up to 4 years | Duration of response (DR) was analyzed for all patients in whom a response had been observed and was calculated from the date of the first documentation of response to the date of PD or further therapy or death |
| Time to Progression | From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years | Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD. |
Countries
France, Spain
Participant flow
Recruitment details
39 patients were enrolled at 7 sites in Spain and France and 36 of them were treated with the combination of plitidepsin, bortezomib (BTZ) and dexamethasone (DXM). Patients who participated between 18Jun2014-30Aug2018 (cutoff date). The first dose of the first cycle was administered on 7Jul2014 and the last cycle was administered on 25May2018
Pre-assignment details
Age≥18;Consent Informed (CI) signed;Confirmed diagnosis of MM according to the Durie-Salmon criteria;Relapsed and/or refractory disease;Eastern Cooperative Oncology Group performance status (ECOG PS)≤2
Participants by arm
| Arm | Count |
|---|---|
| Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles | 8 |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles | 4 |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles | 27 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Cohort 1: Dose Level 1 | Progressive disease | 6 | 0 | 0 |
| Cohort 1: Dose Level 1 | Treatment-related adverse event | 1 | 0 | 0 |
| Cohort 1: Dose Level 1 | Withdrawal by Subject | 1 | 0 | 0 |
| Cohort 2: Dose Level 2 | Physician Decision | 0 | 1 | 0 |
| Cohort 2: Dose Level 2 | Progressive disease | 0 | 2 | 0 |
| Cohort 2: Dose Level 2 | Treatment-related adverse event | 0 | 1 | 0 |
| Cohort 3: Dose Level 3 | Death | 0 | 0 | 1 |
| Cohort 3: Dose Level 3 | Never were treated | 0 | 0 | 3 |
| Cohort 3: Dose Level 3 | Non-treatment related adverse event | 0 | 0 | 1 |
| Cohort 3: Dose Level 3 | Physician Decision | 0 | 0 | 1 |
| Cohort 3: Dose Level 3 | Progressive disease | 0 | 0 | 15 |
| Cohort 3: Dose Level 3 | Treatment-related adverse event | 0 | 0 | 3 |
| Cohort 3: Dose Level 3 | Withdrawal by Subject | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) | Total | Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 21 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 18 Participants | 14 Participants |
| Age, Continuous | 67 years | 68 years | 66 years | 64 years |
| Agents of prior chemotherapy | 5.0 Agents of chemotherapy | 6.5 Agents of chemotherapy | 7.0 Agents of chemotherapy | 8.0 Agents of chemotherapy |
| Best response to last prior anticancer therapy CR | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Best response to last prior anticancer therapy PD | 0 Participants | 1 Participants | 9 Participants | 8 Participants |
| Best response to last prior anticancer therapy PR | 0 Participants | 3 Participants | 12 Participants | 9 Participants |
| Best response to last prior anticancer therapy SD | 0 Participants | 2 Participants | 4 Participants | 2 Participants |
| Best response to last prior anticancer therapy UK | 0 Participants | 0 Participants | 5 Participants | 5 Participants |
| Best response to last prior anticancer therapy VGPR | 3 Participants | 2 Participants | 7 Participants | 2 Participants |
| Body surface area | 1.7 m^2 | 1.8 m^2 | 1.8 m^2 | 1.8 m^2 |
| Disease status with respect to last prior therapy Relapsed | 2 Participants | 2 Participants | 15 Participants | 11 Participants |
| Disease status with respect to last prior therapy Total refractory | 2 Participants | 6 Participants | 24 Participants | 16 Participants |
| Durie-Salmon stage at diagnosis Stage I | 0 Participants | 2 Participants | 3 Participants | 1 Participants |
| Durie-Salmon stage at diagnosis Stage II | 1 Participants | 5 Participants | 12 Participants | 6 Participants |
| Durie-Salmon stage at diagnosis Stage III | 3 Participants | 1 Participants | 24 Participants | 20 Participants |
| Durie-Salmon subclassification at diagnosis Substage A | 3 Participants | 8 Participants | 30 Participants | 19 Participants |
| Durie-Salmon subclassification at diagnosis Substage B | 1 Participants | 0 Participants | 9 Participants | 8 Participants |
| ECOG PS PS 0 | 2 Participants | 1 Participants | 8 Participants | 5 Participants |
| ECOG PS PS 1 | 2 Participants | 6 Participants | 29 Participants | 21 Participants |
| ECOG PS PS 2 | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| International Staging System at diagnosis Stage I | 0 Participants | 6 Participants | 14 Participants | 8 Participants |
| International Staging System at diagnosis Stage II | 1 Participants | 0 Participants | 6 Participants | 5 Participants |
| International Staging System at diagnosis Stage III | 2 Participants | 1 Participants | 10 Participants | 7 Participants |
| International Staging System at diagnosis Unknown | 1 Participants | 1 Participants | 9 Participants | 7 Participants |
| Lines of prior chemotherapy | 2 lines of chemotherapy | 2 lines of chemotherapy | 4 lines of chemotherapy | 5 lines of chemotherapy |
| Multiple myeloma type at diagnosis Non-secretory | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Multiple myeloma type at diagnosis Oligosecretory | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Multiple myeloma type at diagnosis Secretory | 4 Participants | 7 Participants | 36 Participants | 25 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 8 Participants | 36 Participants | 24 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 18 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 21 Participants | 15 Participants |
| Time from diagnosis to first infusion | 55.8 months | 65.3 months | 64.5 months | 64.5 months |
| Time from last progressive disease to first infusion | 5.3 months | 1.6 months | 1.6 months | 1.6 months |
| Weight | 65.1 Kg | 70.9 Kg | 70.8 Kg | 72.0 Kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 8 | 0 / 4 | 1 / 24 |
| other Total, other adverse events | 8 / 8 | 4 / 4 | 24 / 24 |
| serious Total, serious adverse events | 5 / 8 | 3 / 4 | 12 / 24 |
Outcome results
Primary
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
DLTs were defined as: Hematological Toxicity * Grade 3/4 neutropenia associated with fever or lasting\>7 days related to the study treatment * Grade 3/4 thrombocytopenia accompanied by grade 3/4 hemorrhage * Extensive bone marrow (BM) infiltration, DLT was defined as grade 4 thrombocytopenia with grade 3/4 hemorrhage or grade 4 neutropenia lasting \>7 days or with fever Non-hematological Toxicity * Grade 3/4 nausea and vomiting refractory to antiemetic therapy * Grade≥3 muscular Adverse events (AE) (myalgia, muscular weakness, muscle cramps, myopathy) * Grade≥3 alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) lasting more than 1 week * Grade≥3 bilirubin increase * Grade≥3 creatine phosphokinase (CPK) increase * Cardiac toxicity * Symptomatic or treatment-requiring grade ≥1 cardiac arrhythmia related to plitidepsin * Grade≥1 left ventricular systolic dysfunction related to plitidepsin * Neuropathic pain and peripheral sensory neuropathy related to BTZ
Time frame: After 28-day cycle
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 2 Participants |
Primary
Recommended Dose of Bortezomib in Combination With Plitidepsin and Dexamethasone
To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle.
Time frame: After 28-day cycle
Population: Participants who received at least 1 dose study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Recommended Dose of Bortezomib in Combination With Plitidepsin and Dexamethasone | 1.3 mg/m^2 of bortezomib |
Primary
Recommended Dose of Dexamethasone in Combination With Plitidepsin and Bortezomib
To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle.
Time frame: After 28-day cycle
Population: Participants who received at least 1 dose study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Recommended Dose of Dexamethasone in Combination With Plitidepsin and Bortezomib | 40.0 mg of dexamethasone |
Primary
Recommended Dose of Plitidepsin in Combination With Bortezomib and Dexamethasone
To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle.
Time frame: After 28-day cycle
Population: Participants who received at least 1 dose study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Recommended Dose of Plitidepsin in Combination With Bortezomib and Dexamethasone | 5.0 mg/m^2 of plitidepsin |
Secondary
Duration of Response
Duration of response (DR) was analyzed for all patients in whom a response had been observed and was calculated from the date of the first documentation of response to the date of PD or further therapy or death
Time frame: From the date of the first documentation of response to the date of PD or further therapy or death, up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Duration of Response | 21.0 months |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Duration of Response | 12.6 months |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Duration of Response | 12.3 months |
Secondary
Event-free Survival
Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance
Time frame: From the date of first infusion to the date of documented PD or death, up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Event-free Survival | 10.4 months |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival | 13.6 months |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival | 2.8 months |
Secondary
Event-free Survival Rates
Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance
Time frame: from the date of first infusion to the date of documented PD or death, up to 4 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| All Participants | Event-free Survival Rates | At 12 months | 35.7 percentage of participants |
| All Participants | Event-free Survival Rates | At 3 months | 85.7 percentage of participants |
| All Participants | Event-free Survival Rates | At 6 months | 71.4 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival Rates | At 12 months | 66.7 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival Rates | At 3 months | 100.0 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival Rates | At 6 months | 66.7 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival Rates | At 12 months | 13.3 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival Rates | At 3 months | 44.4 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Event-free Survival Rates | At 6 months | 26.7 percentage of participants |
Secondary
Overall Response Rate
Overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR) according to the International Myeloma Working Group (IMWG) criteria
Time frame: Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Overall Response Rate | 57.1 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Overall Response Rate | 66.7 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Overall Response Rate | 22.2 percentage of participants |
Secondary
Progression-free Survival
Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first
Time frame: from the date of the first infusion to the date of documented PD or death, up to 4 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Progression-free Survival | 10.4 months |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival | 13.6 months |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival | 2.8 months |
Secondary
Progression-free Survival Rates
Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first
Time frame: From the date of the first infusion to the date of documented PD or death, up to 4 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| All Participants | Progression-free Survival Rates | At 6 months | 71.4 percentage of participants |
| All Participants | Progression-free Survival Rates | At 3 months | 85.7 percentage of participants |
| All Participants | Progression-free Survival Rates | At 12 months | 35.7 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival Rates | At 6 months | 66.7 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival Rates | At 3 months | 100.0 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival Rates | At 12 months | 66.7 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival Rates | At 3 months | 44.4 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival Rates | At 12 months | 13.3 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Progression-free Survival Rates | At 6 months | 26.7 percentage of participants |
Secondary
Response According to International Myeloma Working Group Criteria
Stringent complete response (sCR) normal Free Light Chains (FLC) ratio. No clonal cells Complete response (CR) no serum/urine M-protein, no evidence of soft tissue plasmacytoma. \<5% clonal plasma cells 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
Time frame: Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Response According to International Myeloma Working Group Criteria | sCR | 0 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | CR | 1 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | VGPR | 2 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | PR | 1 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | MR | 1 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | SD≥4 months | 1 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | SD<4 months | 0 Participants |
| All Participants | Response According to International Myeloma Working Group Criteria | PD | 1 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | VGPR | 0 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | SD<4 months | 0 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | PR | 1 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | MR | 1 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | SD≥4 months | 0 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | sCR | 1 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | CR | 0 Participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | PD | 0 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | VGPR | 1 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | CR | 0 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | sCR | 1 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | PR | 2 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | SD<4 months | 7 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | SD≥4 months | 2 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | MR | 1 Participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Response According to International Myeloma Working Group Criteria | PD | 4 Participants |
Secondary
Time to Progression
Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.
Time frame: From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Progression | 10.4 months |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression | 13.6 months |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression | 2.8 months |
Secondary
Time to Progression Rates
Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.
Time frame: From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| All Participants | Time to Progression Rates | At 6 months | 71.4 percentage of participants |
| All Participants | Time to Progression Rates | At 3 months | 85.7 percentage of participants |
| All Participants | Time to Progression Rates | At 12 months | 35.7 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression Rates | At 6 months | 66.7 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression Rates | At 3 months | 100.0 percentage of participants |
| Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression Rates | At 12 months | 66.7 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression Rates | At 3 months | 44.4 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression Rates | At 12 months | 13.3 percentage of participants |
| Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) | Time to Progression Rates | At 6 months | 26.7 percentage of participants |