Trial Outcomes & Findings for Trial of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Bortezomib and Lenalidomide (NCT NCT03117361)

Last Updated: 2020-12-02

Results Overview

Partial response (PR): ≥50% reduction in serum M-protein and reduction of 24-hour urine M-protein by 90% or to \<200 mg/24h Minimal response (MR): ≥25% but ≤49% reduction of serum M-protein and reduction of 24h urine M-protein 50-89%. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions Stable disease (SD): not meet the criteria for PR, MR or PD Primary analysis should have been done once a total of 64 patients have received plitidepsin+BTZ+DXM with one futility analysis planned after the inclusion of 20 evaluable patients that had completed two full treatment cycles. Only 10 patients were treatedand 8 evaluable for the primary endpoint (ORR according to IMWG criteria). As a result of slow patient accrual, the study was closed before reaching the target enrollment

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

10 participants

Primary outcome timeframe

From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Results posted on

2020-12-02

Participant Flow

Patients participated between 15May2017 - 30Jul2018 (last follow-up cutoff date). The 1st dose/1st cycle was administered on 15May2017 and the last dose/last cycle on 23Jul2018. At cutoff date 10 patients had been included and treated with plitidepsin+BTZ+DXM and they were evaluable for safety. 8 of these were evaluable for the efficacy endpoint

IC signed;Age≥18 years;confirmed diagnosis of MM,ECOG PS≤2;LVEF≥45%;negative pregnancy test

Participant milestones

Participant milestones
Measure	Experimental Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Study STARTED	10
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Experimental Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Study Progressive disease	5
Overall Study Death	1
Overall Study Physician Decision	2
Overall Study On study treatment at the end of study	1
Overall Study Treatment-related adverse event	1

Baseline Characteristics

Trial of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Bortezomib and Lenalidomide

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Experimental n=10 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants
Age, Continuous	59 years n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants
Race/Ethnicity, Customized White	7 Participants n=5 Participants
Race/Ethnicity, Customized Other	3 Participants n=5 Participants
Region of Enrollment Italy	4 Participants n=5 Participants
Region of Enrollment France	3 Participants n=5 Participants
Region of Enrollment Spain	3 Participants n=5 Participants
ECOG PS PS 0	5 Participants n=5 Participants
ECOG PS PS 1	4 Participants n=5 Participants
ECOG PS PS 2	1 Participants n=5 Participants
Multiple myeloma type at diagnosis Secretory IgA	2 Participants n=5 Participants
Multiple myeloma type at diagnosis Secretory IgG	4 Participants n=5 Participants
Multiple myeloma type at diagnosis Secretory Kappa light-chain disease	2 Participants n=5 Participants
Multiple myeloma type at diagnosis Secretory Lambda light-chain disease	2 Participants n=5 Participants
Durie-Salmon stage and subclassification at diagnosis IIA	2 Participants n=5 Participants
Durie-Salmon stage and subclassification at diagnosis IIIA	3 Participants n=5 Participants
Durie-Salmon stage and subclassification at diagnosis IIIB	1 Participants n=5 Participants
Durie-Salmon stage and subclassification at diagnosis Missing	4 Participants n=5 Participants
ISS stage at diagnosis ISS I	1 Participants n=5 Participants
ISS stage at diagnosis ISS II	1 Participants n=5 Participants
ISS stage at diagnosis ISS III	4 Participants n=5 Participants
ISS stage at diagnosis Not done	4 Participants n=5 Participants
R-ISS stage at study entry Stage II	3 Participants n=5 Participants
R-ISS stage at study entry Stage III	3 Participants n=5 Participants
R-ISS stage at study entry Non available genetic results	4 Participants n=5 Participants
Cytogenetic at study entry High risk	2 Participants n=5 Participants
Cytogenetic at study entry Standard risk	4 Participants n=5 Participants
Cytogenetic at study entry Non available genetic results	4 Participants n=5 Participants
Disease status with respect to last prior therapy Primary Refractory	7 Participants n=5 Participants
Disease status with respect to last prior therapy Relapsed and refractory	3 Participants n=5 Participants
Best response to last prior anticancer therapy PR	2 Participants n=5 Participants
Best response to last prior anticancer therapy MR	1 Participants n=5 Participants
Best response to last prior anticancer therapy SD	2 Participants n=5 Participants
Best response to last prior anticancer therapy PD	5 Participants n=5 Participants
Prior HSCT Autologous	6 Participants n=5 Participants
Prior HSCT Autologous and allogenic	2 Participants n=5 Participants
Prior HSCT No	2 Participants n=5 Participants
Lines of prior chemotherapy 3 lines	1 Participants n=5 Participants
Lines of prior chemotherapy 4 lines	2 Participants n=5 Participants
Lines of prior chemotherapy 5 lines	4 Participants n=5 Participants
Lines of prior chemotherapy 8 lines	2 Participants n=5 Participants
Lines of prior chemotherapy 9 lines	1 Participants n=5 Participants
Weight	71.4 kg n=5 Participants
Height	167.1 cm n=5 Participants
Body surface area	1.8 m^2 n=5 Participants
Time from diagnosis to first plitidepsin infusion	70.7 months n=5 Participants
Time from last progressive disease to first infusion	5.3 weeks n=5 Participants
Lines of prior chemotherapy	5 Lines n=5 Participants
Agents of prior chemotherapy	9 Agents n=5 Participants
TTP to last anticancer therapy	3.4 months n=5 Participants

PRIMARY outcome

Timeframe: From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Response PR	1 Participants
Overall Response MR	1 Participants
Overall Response SD	5 Participants
Overall Response PD	1 Participants

PRIMARY outcome

Timeframe: From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

The primary endpoint was overall response rate (ORR) (including stringent complete response \[sCR\], complete response \[CR\], very good partial response \[VGPR\] and partial response \[PR\]), according to the IMWG response criteria.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Response Rate	12.5 percentage of participants Interval 0.3 to 52.7

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Clinical benefit rate defined as minimal response or better

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Clinical Benefit Rate	25.0 percentage of participants Interval 3.2 to 65.1

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Disease control rate defined as stable disease \[SD\] or better

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Disease Control Rate	87.5 percentage of participants Interval 47.3 to 99.7

SECONDARY outcome

Timeframe: From the date of first documentation of response to the date of disease progression, up to 100 weeks

Population: Only one patient achieved a partial response

Duration of Response defined as the time, in months, from the date of first documentation of response to the date of disease progression. Response was assessed according to the IMWG classification response criteria.

Outcome measures

Outcome measures
Measure	Experimental n=1 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Duration of Response	9.2 months

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death due to PD, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Time to progression (TTP) was defined as the time, in months, from the date of the first infusion to the date of documented PD or death due to PD. TTP was to be censored on the date of the last tumor assessment or on the date of the first drug administration if there were no tumor assessments. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Time to Progression	2.7 months Interval 0.7 to upper limit was not estimable due to few participants with events

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death due to PD, up to 3 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Progression disease was defined as documented PD or death due to PD Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Progression Disease at 3 Months	37.5 percentage of participants Interval 4.0 to 71.0

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death due to PD, up to 6 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Progression Disease at 6 Months	25.0 percentage of participants Interval 0.0 to 55.0

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death due to PD, up to 12 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Progression Disease at 12 Months	25.0 percentage of participants Interval 0.0 to 55.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of documented PD, or death (of any cause), up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Progression-free Survival	2.7 months Interval 0.7 to upper limit was not estimable due to few participants with events

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of documented PD, or death (of any cause), up to 3 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Progression-free Survival at 3 Months	37.5 percentage of participants Interval 4.0 to 71.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of documented PD, or death (of any cause), up to 6 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Progression-free Survival at 6 Months	25.0 percentage of participants Interval 0.0 to 55.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of documented PD, or death (of any cause), up to 12 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Progression-free Survival at 12 Months	25.0 percentage of participants Interval 0.0 to 55.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Event-free survival (EFS) was defined as the time, in months, from the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death. The censoring rules defined above for PFS were used for EFS

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Event-free Survival	2.7 months Interval 0.7 to upper limit was not estimable due to few participants with events

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 3 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. rogressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Event-free Survival at 3 Months	37.5 percentage of participants Interval 4.0 to 71.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 6 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Event-free Survival at 6 Months	25.0 percentage of participants Interval 0.0 to 55.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 12 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Event-free Survival at 12 Months	25.0 percentage of participants Interval 0.0 to 55.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 100 weeks

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Overall survival (OS) was defined as the time, in months, from the date of first drug administration to the date of death (of any cause) or last patient contact (in this case, survival was to be censored on that date).

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Survival	NA months Interval 2.3 to Median and upper limit was not estimable due to few participants with events

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 6 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Overall survival (OS) was defined as death of any cause.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Overall Survival at 6 Months	55.6 percentage of participants Interval 6.9 to 100.0

SECONDARY outcome

Timeframe: From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 12 months

Population: 1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Overall survival (OS) was defined as death of any cause.

Outcome measures

Outcome measures
Measure	Experimental n=8 Participants Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Percentage of Participants With Overall Survival at 12 Months	55.6 percentage of participants Interval 6.9 to 100.0

Adverse Events

Experimental

Serious events: 5 serious events

Other events: 10 other events

Deaths: 3 deaths

Serious adverse events

Serious adverse events
Measure	Experimental n=10 participants at risk Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Blood and lymphatic system disorders Anaemia	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Blood and lymphatic system disorders Thrombocytopenia	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Nervous system disorders Sciatica	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Pyrexia	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Gastrointestinal haemorrhage	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Renal and urinary disorders Acute kidney injury	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Musculoskeletal and connective tissue disorders Rhabdomyolysis	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hypercalcaemia	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Cellulitis	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Respiratory tract infection	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years

Other adverse events

Other adverse events
Measure	Experimental n=10 participants at risk Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Respiratory, thoracic and mediastinal disorders Epistaxis	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Vascular disorders Haematoma	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Vascular disorders Hypertension	20.0% 2/10 • Number of events 3 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Surgical and medical procedures Intramedullary rod insertion	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Asthenia/Fatigue	40.0% 4/10 • Number of events 22 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Extravasation	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Malaise	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Oedema peripheral	10.0% 1/10 • Number of events 7 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Peripheral swelling	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
General disorders Pyrexia	40.0% 4/10 • Number of events 6 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Psychiatric disorders Depression	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Injury, poisoning and procedural complications Overdose	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Alanine aminotransferase increased	40.0% 4/10 • Number of events 12 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Antithrombin III decreased	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Aspartate aminotransferase increased	20.0% 2/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Blood cholesterol	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Blood creatine phosphokinase increased	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Blood creatinine increased	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Blood lactate dehydrogenase increased	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Neutrophil count decreased	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Investigations Weight decreased	20.0% 2/10 • Number of events 3 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Respiratory, thoracic and mediastinal disorders Catarrh	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Respiratory, thoracic and mediastinal disorders Cough	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Respiratory, thoracic and mediastinal disorders Respiratory failure	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Blood and lymphatic system disorders Anaemia	60.0% 6/10 • Number of events 25 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Blood and lymphatic system disorders Neutropenia	30.0% 3/10 • Number of events 5 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Blood and lymphatic system disorders Thrombocytopenia	40.0% 4/10 • Number of events 35 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Nervous system disorders Headache	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Nervous system disorders Neuropathy peripheral	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Nervous system disorders Peripheral sensory neuropathy	20.0% 2/10 • Number of events 14 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Nervous system disorders Sciatica	10.0% 1/10 • Number of events 4 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Nervous system disorders Seizure	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Eye disorders Cataract	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Ear and labyrinth disorders Vertigo	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Constipation	20.0% 2/10 • Number of events 3 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Diarrhoea	20.0% 2/10 • Number of events 7 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Gastric disorder	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Gingival bleeding	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Mouth haemorrhage	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Nausea	50.0% 5/10 • Number of events 8 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Gastrointestinal disorders Vomiting	20.0% 2/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Renal and urinary disorders Renal failure	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Musculoskeletal and connective tissue disorders Arthralgia	10.0% 1/10 • Number of events 7 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Musculoskeletal and connective tissue disorders Back pain	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Musculoskeletal and connective tissue disorders Muscular weakness	10.0% 1/10 • Number of events 19 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Musculoskeletal and connective tissue disorders Myalgia	20.0% 2/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Decreased appetite	20.0% 2/10 • Number of events 3 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hypercalcaemia	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hyperglycaemia	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hyperuricaemia	20.0% 2/10 • Number of events 3 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hypocalcaemia	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hypokalaemia	20.0% 2/10 • Number of events 4 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Metabolism and nutrition disorders Hypomagnesaemia	20.0% 2/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Folliculitis	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Gastroenteritis	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Herpes zoster	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Influenza	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Nasopharyngitis	10.0% 1/10 • Number of events 1 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Infections and infestations Respiratory tract infection	10.0% 1/10 • Number of events 2 • From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years

Additional Information

Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit.

Pharma Mar, S.A.

Phone: +34 918466000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review.
Publication restrictions are in place

Restriction type: OTHER