ADMYRE: Aplidin - Dexamethasone in Relapsed/Refractory Myeloma

• Sponsor: PharmaMar (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01102426
• Collaborator: (none)
• Enrollment: 255
• Locations: 82
• Arms: 2
• Duration (Months): 89
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Study of Plitidepsin in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory Multiple Myeloma	Drug: Plitidepsin; Drug: Dexamethasone	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 255 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination With Dexamethasone vs. Dexamethasone Alone in Patients With Relapsed/Refractory Multiple Myeloma
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Plitidepsin+Dexamethasone plitidepsin + dexamethasone combination	Drug: Plitidepsin; 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.; Other Names: APLIDIN (plitidepsin) ; Drug: Dexamethasone; 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.; Other Names: DXN
Active Comparator: Dexamethasone dexamethasone single agent	Drug: Dexamethasone; 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.; Other Names: DXN

Outcome Measures

Primary Outcome Measures

1. 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

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1107	Tuscaloosa	Alabama	United States
2	1103	Los Angeles	California	United States
3	1105	Jacksonville	Florida	United States
4	1102	New York	New York	United States
5	1104	Canton	Ohio	United States
6	108	Adelaide		Australia
7	102	Canberra		Australia
8	101	Geelong		Australia
9	105	Parkville		Australia
10	106	Perth		Australia
11	104	South Brisbane		Australia
12	109	Woodville		Australia
13	202	Graz		Austria
14	204	Innsbruck		Austria
15	203	Salzburg		Austria
16	201	Wien		Austria
17	205	Wien		Austria
18	208	Wien		Austria
19	304	Brugge		Belgium
20	301	Brussels		Belgium
21	303	Brussels		Belgium
22	302	Gent		Belgium
23	502	Brno		Czechia
24	503	Hradec Kralove		Czechia
25	501	Praha		Czechia
26	601	Lille		France
27	602	Nantes		France
28	606	Rouen		France
29	604	Vandœuvre-lès-Nancy		France
30	709	Düsseldorf		Germany
31	705	Essen		Germany
32	706	Frankfurt		Germany
33	707	Frankfurt		Germany
34	708	Freiburg		Germany
35	703	Heidelberg		Germany
36	702	Munchen		Germany
37	704	Würzburg		Germany
38	1301	Athens		Greece
39	1303	Patras		Greece
40	1302	Thessaloniki		Greece
41	1401	Dublin		Ireland
42	806	Bari		Italy
43	801	Genova		Italy
44	805	Reggio Emilia		Italy
45	803	Rozzano		Italy
46	804	San Giovanni Rotondo		Italy
47	802	Torino		Italy
48	1502	Anyang		Korea, Republic of
49	1501	Daejeon		Korea, Republic of
50	1507	Hwasun		Korea, Republic of
51	1506	Incheon		Korea, Republic of
52	1505	Jeonju		Korea, Republic of
53	1508	Seongnam		Korea, Republic of
54	1503	Seoul		Korea, Republic of
55	1504	Seoul		Korea, Republic of
56	1509	Seoul		Korea, Republic of
57	901	Rotterdam		Netherlands
58	902	Rotterdam		Netherlands
59	1601	Christchurch		New Zealand
60	1602	Takapuna		New Zealand
61	1704	Opole		Poland
62	1703	Warszawa		Poland
63	1802	Braga		Portugal
64	1801	Porto		Portugal
65	2001	San Juan		Puerto Rico
66	1201	Barcelona		Spain
67	1203	Barcelona		Spain
68	1209	Barcelona		Spain
69	1207	Madrid		Spain
70	1210	Madrid		Spain
71	1206	Murcia		Spain
72	1204	Palma de Mallorca		Spain
73	1208	Salamanca		Spain
74	1202	San Sebastián		Spain
75	1205	Valencia		Spain
76	1901	Taipei		Taiwan
77	1902	Taipei		Taiwan
78	1903	Taipei		Taiwan
79	1003	Bournemouth		United Kingdom
80	1004	Bradford		United Kingdom
81	1001	London		United Kingdom
82	1005	Nottingham		United Kingdom

Sponsors and Collaborators

• PharmaMar

Investigators

• Principal Investigator: Óscar F. Ballester, M.D., Edwards Comprehensive Cancer Center, Marshall University (Huntington)
• Principal Investigator: Rubén Niesvizky, M.D., NY Presbyterian Hosp. - Cornell University - NY

Study Documents (Full-Text)

• Study Protocol - Jul 10, 2017
• Statistical Analysis Plan - Jun 15, 2017

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT01102426
• Other Study ID Numbers: APL-C-001-09
• First Posted: Apr 13, 2010
• Last Update Posted: Nov 10, 2020
• Last Verified: Oct 1, 2020

• Keywords provided by PharmaMar: Multiple Myeloma; Aplidin; plitidepsin; dexamethasone
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone

Study Results

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.

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Period Title: Overall Study
STARTED	171	84
COMPLETED	6	3
NOT COMPLETED	165	81

Baseline Characteristics

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone	Total
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.	Total of all reporting groups
Overall Participants	171	84	255
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	88 51.5%	36 42.9%	124 48.6%
>=65 years	83 48.5%	48 57.1%	131 51.4%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	65	65
Sex: Female, Male (Count of Participants)
Female	74 43.3%	49 58.3%	123 48.2%
Male	97 56.7%	35 41.7%	132 51.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	6 3.5%	1 1.2%	7 2.7%
Czechia	23 13.5%	10 11.9%	33 12.9%
United Kingdom	12 7%	6 7.1%	18 7.1%
Portugal	2 1.2%	1 1.2%	3 1.2%
Spain	13 7.6%	7 8.3%	20 7.8%
Greece	12 7%	7 8.3%	19 7.5%
New Zealand	7 4.1%	1 1.2%	8 3.1%
Austria	21 12.3%	7 8.3%	28 11%
South Korea	8 4.7%	4 4.8%	12 4.7%
Netherlands	5 2.9%	4 4.8%	9 3.5%
ECOG PS (Count of Participants)
PS 0	68 39.8%	31 36.9%	99 38.8%
PS 1	74 43.3%	42 50%	116 45.5%
PS 2	28 16.4%	11 13.1%	39 15.3%
PS 3	1 0.6%	0 0%	1 0.4%
MM type at diagnosis (Count of Participants)
Non Secretory	6 3.5%	1 1.2%	7 2.7%
Secretory IgA	35 20.5%	21 25%	56 22%
Secretory IgD	1 0.6%	1 1.2%	2 0.8%
Secretory IgG	101 59.1%	51 60.7%	152 59.6%
Secretory IgM	1 0.6%	0 0%	1 0.4%
Secretory Light chain disease	27 15.8%	10 11.9%	37 14.5%
Durie-Salmon stage at diagnosis (Count of Participants)
Stage A	0 0%	1 1.2%	1 0.4%
Stage IA	21 12.3%	9 10.7%	30 11.8%
Stage IB	0 0%	2 2.4%	2 0.8%
Stage II	3 1.8%	1 1.2%	4 1.6%
Stage IIA	44 25.7%	20 23.8%	64 25.1%
Stage IIB	1 0.6%	0 0%	1 0.4%
Stage III	2 1.2%	1 1.2%	3 1.2%
Stage IIIA	85 49.7%	43 51.2%	128 50.2%
Stage IIIB	14 8.2%	7 8.3%	21 8.2%
Not Durie-Salmon stage at diagnosis	1 0.6%	0 0%	1 0.4%
International Staging System at diagnosis (Count of Participants)
Stage I	72 42.1%	33 39.3%	105 41.2%
Stage II	41 24%	18 21.4%	59 23.1%
Stage III	23 13.5%	15 17.9%	38 14.9%
Not stage at diagnosis	35 20.5%	18 21.4%	53 20.8%
Cytogenetic risk group at diagnosis (Count of Participants)
Standard risk	34 19.9%	21 25%	55 21.6%
High risk	38 22.2%	16 19%	54 21.2%
NA/ND/UK	99 57.9%	47 56%	146 57.3%
Prior radiotherapy (Count of Participants)
Yes	68 39.8%	35 41.7%	103 40.4%
No	103 60.2%	49 58.3%	152 59.6%
Hb (g/dL) [Median (Full Range) ]
Median (Full Range) [g/dL]	10.4	10.1	10.3
Platelets (platelets*10^9/L) [Median (Full Range) ]
Median (Full Range) [platelets*10^9/L]	140	154	144
CrCL (mL/min) [Median (Full Range) ]
Median (Full Range) [mL/min]	72.9	69.4	71.9
Time from first diagnosis to randomization (months) [Median (Full Range) ]
Median (Full Range) [months]	71.8	70	71.3
Time from last PD/relapse to first study dose (weeks) [Median (Full Range) ]
Median (Full Range) [weeks]	6.1	6.4	6.2
Beta-2 microglobulin (mg/L) [Median (Full Range) ]
Median (Full Range) [mg/L]	4.1	4.2	4.1
Number of lines of prior systemic therapy (lines) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [lines]	4	4	4

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) as Per Intention-to-treat (ITT)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Median (95% Confidence Interval) [months]	2.6	1.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0054
	Comments	Cox regression: HR p=0.0062
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.447 to 0.885
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percentage of Participants With Progression Free Survival (PFS) as Per Intention-to-treat (ITT) at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	20.0 11.7%	10.0 11.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0618
	Comments
	Method	Normal approximation
	Comments

3. Secondary Outcome

Title	Progression-free Survival (Investigator Assessment)
Description	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

Outcome Measure Data

Analysis Population Description

All Randomized Patients

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Median (95% Confidence Interval) [months]	2.9	1.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Cox regression HR: p<0.0001
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.512
	Confidence Interval	(2-Sided) 95%; 0.382 to 0.686
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Progression-free Survival (Investigator Assessment) at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	26.4 15.4%	8.1 9.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Normal approximation
	Comments

5. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

All Randomized Patients

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Median (95% Confidence Interval) [months]	11.6	8.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments	Pre-specified
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1261
	Comments	Cox regression HR: p=0.1273
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.797
	Confidence Interval	(2-Sided) 95%; 0.596 to 1.067
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With Overall Survival at 12 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	48.3 28.2%	42.1 50.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3625
	Comments
	Method	Normal approximation
	Comments

7. Secondary Outcome

Title	Percentage of Participants With Overall Survival at 24 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	30.8 18%	21.0 25%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1037
	Comments
	Method	Normal approximation
	Comments

8. Secondary Outcome

Title	Duration of Response (Independent Review Committee)
Description	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

Outcome Measure Data

Analysis Population Description

Patients with documentation of response

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	39	3
Median (95% Confidence Interval) [months]	3.7	1.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1015
	Comments	Cox regression HR: 0.1247
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.384
	Confidence Interval	(2-Sided) 95%; 0.113 to 1.303
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Participants With Duration of Response (Independent Review Committee) at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

Patients with documentation of response

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	39	3
Number (95% Confidence Interval) [percentage of participants]	41.2 24.1%	0.0 0%

10. Secondary Outcome

Title	Duration of Response (Investigator Assessment)
Description	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

Outcome Measure Data

Analysis Population Description

Patients with documentation of response

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	51	1
Median (95% Confidence Interval) [months]	5.1	0.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments	Pre-specified
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0001
	Comments	Cox regression HR: 0.0105
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; 0.004 to 0.479
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percentage of Participants With Duration of Response (Investigator Assessment) at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

Patients with documentation of response

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	51	1
Number (95% Confidence Interval) [percentage of participants]	38.2 22.3%	0.0 0%

12. Secondary Outcome

Title	Best Overall Response (Independent Review Committee)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
VGR	2 1.2%	0 0%
PR	15 8.8%	1 1.2%
MR	22 12.9%	2 2.4%
SD	43 25.1%	21 25%
PD	41 24%	35 41.7%
NE	48 28.1%	25 29.8%

13. Secondary Outcome

Title	Overall Response Rate (Independent Review Committee)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	22.8 13.3%	3.6 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

14. Secondary Outcome

Title	Overall Response Rate (Independent Review Committee) Excluding MR
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	9.9 5.8%	1.2 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Fisher Exact
	Comments

15. Secondary Outcome

Title	Best Overall Response (Investigator Assessment)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
VGPR	4 2.3%	0 0%
PR	16 9.4%	1 1.2%
MR	31 18.1%	0 0%
SD	61 35.7%	31 36.9%
PD	37 21.6%	39 46.4%
NE	22 12.9%	13 15.5%

16. Secondary Outcome

Title	Overall Response Rate (Investigator Assessment)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	29.8 17.4%	1.2 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

17. Secondary Outcome

Title	Overall Response Rate (Investigator Assessment) Excluding MR
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Plitidepsin+Dexamethasone	Dexamethasone
Arm/Group Description	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.	dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
Measure Participants	171	84
Number (95% Confidence Interval) [percentage of participants]	11.7 6.8%	1.2 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Plitidepsin+Dexamethasone, Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 5 years
Adverse Event Reporting Description	Four patients were not treated after randomization in Plitidepsin+Dexamethasone due to 2 deaths, 1 patient refusal and 1 reason not specified. One patient was not treated after randomization in Dexamethasone due to patient refusal
Arm/Group Title	Plitidepsin+Dexamethasone		Dexamethasone
Arm/Group Description	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.		dexamethasone single agent dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.
All Cause Mortality
	Plitidepsin+Dexamethasone		Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	126/167 (75.4%)		74/83 (89.2%)
Serious Adverse Events
	Plitidepsin+Dexamethasone		Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/167 (59.3%)		26/83 (31.3%)
Blood and lymphatic system disorders
Anaemia	3/167 (1.8%)	5	3/83 (3.6%)	4
Disseminated intravascular coagulation	1/167 (0.6%)	1	0/83 (0%)	0
Hyperviscosity syndrome	1/167 (0.6%)	1	0/83 (0%)	0
Pancytopenia	1/167 (0.6%)	1	0/83 (0%)	0
Thrombocytopenia	1/167 (0.6%)	1	0/83 (0%)	0
Cardiac disorders
Atrial fibrillation	2/167 (1.2%)	4	1/83 (1.2%)	1
Cardiac arrest	2/167 (1.2%)	2	0/83 (0%)	0
Cardiac failure	3/167 (1.8%)	3	0/83 (0%)	0
Cardiac failure congestive	1/167 (0.6%)	1	0/83 (0%)	0
Coronary artery disease	1/167 (0.6%)	1	0/83 (0%)	0
Myocardial infarction	1/167 (0.6%)	1	0/83 (0%)	0
Systolic dysfunction	1/167 (0.6%)	1	0/83 (0%)	0
Ventricular arrhythmia	1/167 (0.6%)	1	0/83 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/167 (0.6%)	1	1/83 (1.2%)	1
Diarrhoea	3/167 (1.8%)	3	1/83 (1.2%)	1
Diverticular perforation	1/167 (0.6%)	1	0/83 (0%)	0
Duodenal ulcer	1/167 (0.6%)	1	0/83 (0%)	0
Enteritis	1/167 (0.6%)	1	0/83 (0%)	0
Ileus	1/167 (0.6%)	1	0/83 (0%)	0
Lower gastrointestinal haemorrhage	1/167 (0.6%)	1	0/83 (0%)	0
Nausea	4/167 (2.4%)	4	1/83 (1.2%)	1
Vomiting	6/167 (3.6%)	8	1/83 (1.2%)	1
General disorders
Asthenia	4/167 (2.4%)	4	0/83 (0%)	0
Fatigue	3/167 (1.8%)	3	1/83 (1.2%)	1
General physical health deterioration	2/167 (1.2%)	2	1/83 (1.2%)	1
Malaise	2/167 (1.2%)	2	0/83 (0%)	0
Multi-organ failure	1/167 (0.6%)	1	0/83 (0%)	0
Pain	2/167 (1.2%)	2	1/83 (1.2%)	1
Pyrexia	8/167 (4.8%)	8	1/83 (1.2%)	1
Thrombosis in device	1/167 (0.6%)	1	0/83 (0%)	0
Sudden death	0/167 (0%)	0	1/83 (1.2%)	1
Hepatobiliary disorders
Cholangitis	1/167 (0.6%)	1	0/83 (0%)	0
Cholestasis	1/167 (0.6%)	1	0/83 (0%)	0
Hyperbilirubinaemia	3/167 (1.8%)	3	0/83 (0%)	0
Infections and infestations
Atypical pneumonia	1/167 (0.6%)	1	0/83 (0%)	0
Bacteraemia	1/167 (0.6%)	1	0/83 (0%)	0
Bronchitis	1/167 (0.6%)	1	0/83 (0%)	0
Bronchopneumonia	1/167 (0.6%)	1	2/83 (2.4%)	2
Cellulitis	2/167 (1.2%)	2	0/83 (0%)	0
Clostridium difficile colitis	2/167 (1.2%)	2	0/83 (0%)	0
Device related infection	2/167 (1.2%)	2	0/83 (0%)	0
Device related sepsis	1/167 (0.6%)	1	0/83 (0%)	0
Enterocolitis infectious	1/167 (0.6%)	2	0/83 (0%)	0
Escherichia sepsis	2/167 (1.2%)	2	0/83 (0%)	0
Gastroenteritis	1/167 (0.6%)	1	0/83 (0%)	0
Gastroenteritis viral	1/167 (0.6%)	1	0/83 (0%)	0
Herpes zoster	1/167 (0.6%)	1	0/83 (0%)	0
Infection	1/167 (0.6%)	1	0/83 (0%)	0
Lobar pneumonia	1/167 (0.6%)	1	0/83 (0%)	0
Lower respiratory tract infection	1/167 (0.6%)	2	1/83 (1.2%)	1
Lung infection	2/167 (1.2%)	2	0/83 (0%)	0
Neutropenic sepsis	1/167 (0.6%)	1	0/83 (0%)	0
Pneumocystis jiroveci pneumonia	1/167 (0.6%)	1	0/83 (0%)	0
Pneumonia	15/167 (9%)	18	3/83 (3.6%)	3
Pneumonia fungal	1/167 (0.6%)	1	0/83 (0%)	0
Pneumonia pneumococcal	2/167 (1.2%)	2	0/83 (0%)	0
Pseudomonal bacteraemia	1/167 (0.6%)	1	0/83 (0%)	0
Pseudomonas infection	1/167 (0.6%)	1	0/83 (0%)	0
Respiratory tract infection	3/167 (1.8%)	3	1/83 (1.2%)	1
Sepsis	9/167 (5.4%)	9	2/83 (2.4%)	2
Septic shock	4/167 (2.4%)	4	0/83 (0%)	0
Upper respiratory tract infection	1/167 (0.6%)	1	0/83 (0%)	0
Urinary tract infection	4/167 (2.4%)	4	2/83 (2.4%)	2
Urosepsis	1/167 (0.6%)	1	1/83 (1.2%)	1
Viral infection	1/167 (0.6%)	1	0/83 (0%)	0
Clostridium colitis	0/167 (0%)	0	1/83 (1.2%)	1
Pulmonary tuberculosis	0/167 (0%)	0	1/83 (1.2%)	1
Clostridium difficile infection	1/167 (0.6%)	1	0/83 (0%)	0
Injury, poisoning and procedural complications
Drug administration error	1/167 (0.6%)	1	0/83 (0%)	0
Infusion related reaction	1/167 (0.6%)	1	0/83 (0%)	0
Spinal fracture	1/167 (0.6%)	1	0/83 (0%)	0
Sternal fracture	1/167 (0.6%)	1	0/83 (0%)	0
Transfusion reaction	1/167 (0.6%)	1	0/83 (0%)	0
Wound dehiscence	1/167 (0.6%)	1	0/83 (0%)	0
Clavicle fracture	0/167 (0%)	0	1/83 (1.2%)	1
Hip fracture	0/167 (0%)	0	1/83 (1.2%)	1
Upper limb fracture	0/167 (0%)	0	1/83 (1.2%)	1
Investigations
Alanine aminotransferase increased	7/167 (4.2%)	10	0/83 (0%)	0
Aspartate aminotransferase increased	6/167 (3.6%)	12	0/83 (0%)	0
Blood alkaline phosphatase increased	1/167 (0.6%)	2	0/83 (0%)	0
Blood creatine phosphokinase MB increased	1/167 (0.6%)	1	0/83 (0%)	0
Blood creatine phosphokinase increased	6/167 (3.6%)	9	0/83 (0%)	0
Electrocardiogram QT prolonged	3/167 (1.8%)	3	0/83 (0%)	0
Gamma-glutamyltransferase increased	2/167 (1.2%)	4	0/83 (0%)	0
Hepatic enzyme abnormal	1/167 (0.6%)	1	0/83 (0%)	0
Troponin I increased	1/167 (0.6%)	1	0/83 (0%)	0
Weight decreased	1/167 (0.6%)	1	0/83 (0%)	0
Plasma cells increased	0/167 (0%)	0	1/83 (1.2%)	1
Metabolism and nutrition disorders
Decreased appetite	1/167 (0.6%)	1	0/83 (0%)	0
Dehydration	3/167 (1.8%)	3	1/83 (1.2%)	1
Diabetes mellitus	1/167 (0.6%)	1	0/83 (0%)	0
Electrolyte imbalance	1/167 (0.6%)	1	0/83 (0%)	0
Fluid overload	1/167 (0.6%)	1	0/83 (0%)	0
Hypercalcaemia	6/167 (3.6%)	7	2/83 (2.4%)	2
Hyperglycaemia	4/167 (2.4%)	4	0/83 (0%)	0
Hyperkalaemia	1/167 (0.6%)	1	0/83 (0%)	0
Hyperuricaemia	1/167 (0.6%)	1	0/83 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/167 (0.6%)	1	0/83 (0%)	0
Back pain	3/167 (1.8%)	3	0/83 (0%)	0
Bone pain	1/167 (0.6%)	1	1/83 (1.2%)	1
Lumbar spinal stenosis	1/167 (0.6%)	1	0/83 (0%)	0
Mobility decreased	1/167 (0.6%)	1	0/83 (0%)	0
Myalgia	2/167 (1.2%)	2	0/83 (0%)	0
Myopathy	2/167 (1.2%)	2	0/83 (0%)	0
Myopathy toxic	1/167 (0.6%)	2	0/83 (0%)	0
Myositis	1/167 (0.6%)	1	0/83 (0%)	0
Osteolysis	1/167 (0.6%)	1	0/83 (0%)	0
Osteonecrosis of jaw	1/167 (0.6%)	2	0/83 (0%)	0
Pain in extremity	1/167 (0.6%)	1	0/83 (0%)	0
Rhabdomyolysis	2/167 (1.2%)	2	0/83 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oesophageal squamous cell carcinoma	1/167 (0.6%)	1	0/83 (0%)	0
Plasmablastic lymphoma	1/167 (0.6%)	1	0/83 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/167 (0.6%)	1	0/83 (0%)	0
Headache	1/167 (0.6%)	1	0/83 (0%)	0
Paraplegia	1/167 (0.6%)	1	0/83 (0%)	0
Paresis	1/167 (0.6%)	1	0/83 (0%)	0
Presyncope	1/167 (0.6%)	1	0/83 (0%)	0
Quadriparesis	1/167 (0.6%)	1	0/83 (0%)	0
Somnolence	1/167 (0.6%)	1	0/83 (0%)	0
Spinal cord compression	1/167 (0.6%)	1	0/83 (0%)	0
Syncope	2/167 (1.2%)	2	0/83 (0%)	0
Diabetic neuropathy	0/167 (0%)	0	1/83 (1.2%)	1
Memory impairment	0/167 (0%)	0	1/83 (1.2%)	1
Psychiatric disorders
Confusional state	1/167 (0.6%)	1	0/83 (0%)	0
Delirium	1/167 (0.6%)	1	0/83 (0%)	0
Psychotic disorder	1/167 (0.6%)	1	1/83 (1.2%)	1
Renal and urinary disorders
Haematuria	1/167 (0.6%)	1	0/83 (0%)	0
Renal failure	4/167 (2.4%)	4	1/83 (1.2%)	1
Renal failure acute	2/167 (1.2%)	3	3/83 (3.6%)	3
Calculus urinary	0/167 (0%)	0	1/83 (1.2%)	1
Renal failure chronic	0/167 (0%)	0	1/83 (1.2%)	1
Renal impairment	0/167 (0%)	0	1/83 (1.2%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/167 (0.6%)	1	0/83 (0%)	0
Dyspnoea	2/167 (1.2%)	2	1/83 (1.2%)	1
Epistaxis	2/167 (1.2%)	3	2/83 (2.4%)	2
Haemothorax	1/167 (0.6%)	2	0/83 (0%)	0
Hydrothorax	1/167 (0.6%)	1	0/83 (0%)	0
Hypoxia	1/167 (0.6%)	1	0/83 (0%)	0
Pleurisy	1/167 (0.6%)	1	0/83 (0%)	0
Productive cough	1/167 (0.6%)	1	0/83 (0%)	0
Pulmonary haemorrhage	1/167 (0.6%)	1	0/83 (0%)	0
Pulmonary oedema	1/167 (0.6%)	1	0/83 (0%)	0
Lung disorder	0/167 (0%)	0	1/83 (1.2%)	1
Haemoptysis	1/167 (0.6%)	1	0/83 (0%)	0
Vascular disorders
Deep vein thrombosis	1/167 (0.6%)	1	0/83 (0%)	0
Hypotension	1/167 (0.6%)	1	1/83 (1.2%)	1
Subclavian vein thrombosis	1/167 (0.6%)	1	0/83 (0%)	0
Vena cava thrombosis	1/167 (0.6%)	1	0/83 (0%)	0
Venous thrombosis	1/167 (0.6%)	1	0/83 (0%)	0
Thrombophlebitis superficial	1/167 (0.6%)	1	0/83 (0%)	0
Other (Not Including Serious) Adverse Events
	Plitidepsin+Dexamethasone		Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	161/167 (96.4%)		80/83 (96.4%)
Blood and lymphatic system disorders
Anaemia	69/167 (41.3%)	203	34/83 (41%)	97
Neutropenia	12/167 (7.2%)	26	2/83 (2.4%)	3
Thrombocytopenia	15/167 (9%)	47	8/83 (9.6%)	15
Gastrointestinal disorders
Abdominal pain upper	16/167 (9.6%)	16	1/83 (1.2%)	1
Constipation	21/167 (12.6%)	23	5/83 (6%)	7
Diarrhoea	57/167 (34.1%)	80	8/83 (9.6%)	10
Dyspepsia	9/167 (5.4%)	12	4/83 (4.8%)	5
Nausea	76/167 (45.5%)	122	17/83 (20.5%)	19
Vomiting	41/167 (24.6%)	57	3/83 (3.6%)	3
General disorders
Asthenia	32/167 (19.2%)	60	9/83 (10.8%)	11
Chest pain	9/167 (5.4%)	12	2/83 (2.4%)	2
Fatigue	55/167 (32.9%)	95	18/83 (21.7%)	22
Oedema peripheral	31/167 (18.6%)	45	5/83 (6%)	6
Pyrexia	32/167 (19.2%)	50	11/83 (13.3%)	14
Infections and infestations
Nasopharyngitis	5/167 (3%)	5	5/83 (6%)	5
Upper respiratory tract infection	14/167 (8.4%)	19	5/83 (6%)	5
Urinary tract infection	12/167 (7.2%)	13	2/83 (2.4%)	2
Investigations
Alanine aminotransferase increased	22/167 (13.2%)	48	0/83 (0%)	0
Aspartate aminotransferase increased	11/167 (6.6%)	20	0/83 (0%)	0
Blood creatine phosphokinase increased	28/167 (16.8%)	41	0/83 (0%)	0
Electrocardiogram QT prolonged	15/167 (9%)	34	1/83 (1.2%)	1
Weight decreased	12/167 (7.2%)	13	1/83 (1.2%)	1
Platelet count decreased	7/167 (4.2%)	67	5/83 (6%)	21
Metabolism and nutrition disorders
Decreased appetite	34/167 (20.4%)	40	5/83 (6%)	5
Hypercalcaemia	8/167 (4.8%)	9	7/83 (8.4%)	11
Hyperglycaemia	11/167 (6.6%)	16	3/83 (3.6%)	3
Hypokalaemia	19/167 (11.4%)	23	5/83 (6%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	8/167 (4.8%)	8	6/83 (7.2%)	6
Back pain	16/167 (9.6%)	18	15/83 (18.1%)	22
Bone pain	12/167 (7.2%)	13	15/83 (18.1%)	17
Muscular weakness	21/167 (12.6%)	27	3/83 (3.6%)	5
Musculoskeletal pain	12/167 (7.2%)	14	1/83 (1.2%)	1
Myalgia	30/167 (18%)	47	3/83 (3.6%)	3
Nervous system disorders
Headache	18/167 (10.8%)	18	5/83 (6%)	6
Psychiatric disorders
Insomnia	18/167 (10.8%)	23	10/83 (12%)	11
Respiratory, thoracic and mediastinal disorders
Cough	31/167 (18.6%)	42	9/83 (10.8%)	10
Dyspnoea	23/167 (13.8%)	36	3/83 (3.6%)	3
Epistaxis	10/167 (6%)	11	6/83 (7.2%)	8
Vascular disorders
Hypertension	14/167 (8.4%)	17	5/83 (6%)	6
Hypotension	16/167 (9.6%)	17	1/83 (1.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.