Study of Melflufen (Melphalan Flufenamide) in Combination With Daratumumab in Relapsed-Refractory Multiple Myeloma (LIGHTHOUSE)

• ClinicalTrials.gov Identifier: NCT04649060
• Recruitment Status: Terminated
• First Posted: December 2, 2020
• Results First Posted: June 8, 2023
• Last Update Posted: June 8, 2023
• Sponsor: Oncopeptides AB
• Information provided by (Responsible Party): Oncopeptides AB

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Relapsed Multiple Myeloma; Relapsed-Refractory Multiple Myeloma
• Interventions: Drug: Melflufen; Drug: Dexamethasone; Drug: Daratumumab
• Enrollment: 54

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Period Title: Arm A/Arm B Treatment
Started	27	27
Treated [1]	22	26
Completed	0	0
Not Completed	27	27
Reason Not Completed
Adverse Event	0	3
Physician Decision	1	1
Progressive Disease	3	12
Study Terminated by Sponsor	17	10
Patient Request	1	0
Failed Criteria for Treatment Initiation	4	1
Other	1	0
[1] There were 6 randomized patients (5 in Arm A and 1 in Arm B) who never received treatment due to failure to meet treatment initiation criteria and/or consent withdrawal.
Period Title: Crossover (Arm B)
Started	0	2 [1]
Treated	0	2
Completed	0	0
Not Completed	0	2
Reason Not Completed
Adverse Event	0	1
Lost to Follow-up	0	1
[1] There were 2 patients in Arm B who crossed over and received Melflufen+Dexamethasone+Daratumumab after a confirmed disease progression and received at least one dose of treatment.

Baseline Characteristics

Arm/Group Title		Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)	Total
Arm/Group Description		Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Total of all reporting groups
Overall Number of Baseline Participants		27	27	54
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	27 participants	27 participants	54 participants
		64.5; (43 to 80)	66.7; (50 to 83)	65.6; (43 to 83)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	27 participants	27 participants	54 participants
<65		12 44.4%	8 29.6%	20 37.0%
65 - ≤75		13 48.1%	16 59.3%	29 53.7%
>75		2 7.4%	3 11.1%	5 9.3%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	27 participants	27 participants	54 participants
	Female	11 40.7%	10 37.0%	21 38.9%
	Male	16 59.3%	17 63.0%	33 61.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	27 participants	27 participants	54 participants
	Hispanic or Latino	0 0.0%	0 0.0%	0 0.0%
	Not Hispanic or Latino	27 100.0%	27 100.0%	54 100.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	27 participants	27 participants	54 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	27 100.0%	27 100.0%	54 100.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Weight; Mean (Full Range); Unit of measure: Kg
	Number Analyzed	27 participants	27 participants	54 participants
		79.46; (61.0 to 103.8)	78.75; (56.3 to 107.6)	79.1; (56.3 to 107.6)
Height; Mean (Full Range); Unit of measure: Cm
	Number Analyzed	27 participants	27 participants	54 participants
		170.4; (151 to 195)	167.0; (150 to 188)	168.7; (150 to 195)
Eastern Cooperative Oncology Group (ECOG) score [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	27 participants	27 participants	54 participants
	score = 0	8 29.6%	6 22.2%	14 25.9%
	score = 1	18 66.7%	15 55.6%	33 61.1%
	score = 2	1 3.7%	6 22.2%	7 13.0%
		[1] Measure Description: 0=Normal activity, fully active, able to carry on all pre-disease performance without restriction. 1=Symptoms, but fully ambulatory, restricted in physically strenuous but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). 2=Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause, whichever occurred first.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	4.86 [2]; (3.38 to NA)

[1]

The median PFS was not reached in Arm A. There were insufficient numbers of participants with events.

[2]

The upper confidence limit was not available due to insufficient numbers of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0032
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.184
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.650
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Proportion of patients who achieve a best-confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR).
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	59.3; (38.8 to 77.6)	29.6; (13.8 to 50.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.03
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

3. Secondary Outcome

Title	Duration of Response (DOR)
Description	Time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	16	8
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [2]; (2.79 to NA)

[1]

The median DOR was not reached in Arm A and the 95% CI was not available due to insufficient numbers of participants with events.

[2]

The median DOR was not reached in Arm B and the upper confidence limit was not available due to insufficient numbers of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.525
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.418
	Confidence Interval	(2-Sided) 95%; 0.026 to 6.693
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Best Response
Description	Proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD, or non-evaluable (NE).
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Measure Type: Count of Participants; Unit of Measure: Participants
Complete Response (CR)	1 3.7%	0 0.0%
Very Good Partial Response (VGPR)	4 14.8%	3 11.1%
Partial Response (PR)	11 40.7%	5 18.5%
Minimal Response (MR)	3 11.1%	5 18.5%
Stable Disease (SD)	3 11.1%	5 18.5%
Progressive Disease (PD)	1 3.7%	5 18.5%
Not Evaluable (NE)	4 14.8%	4 14.8%

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	The proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR, or MR.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of patients
	70.4; (49.8 to 86.2)	48.1; (28.7 to 68.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0997
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

6. Secondary Outcome

Title	Duration of Clinical Benefit (DOCB)
Description	Time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause. DOCB is defined only for patients with a confirmed MR or better.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	19	13
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [2]; (3.38 to NA)

[1]

The median DOCB was not reached in Arm A and the 95% CI was not available due to insufficient numbers of participants with events.

[2]

The median DOCB was not reached in Arm B and the upper confidence limit was not available due to insufficient numbers of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.016
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.013 to 0.960
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Time to Response (TTR)
Description	Time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥PR.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Mean (Standard Deviation); Unit of Measure: months
	1.8 (1.0)	1.8 (1.1)

8. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time from randomization to the date of the first documented confirmed PD
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [2]; (4.70 to NA)

[1]

The median TTP was not reached in Arm A and the 95% CI was not available due to insufficient numbers of participants with events.

[2]

The median TTP was not reached in Arm B and the upper confidence limit was not available due to insufficient numbers of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0187
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.231
	Confidence Interval	(2-Sided) 95%; 0.063 to 0.846
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Time to Next Treatment (TTNT)
Description	Time from randomization to the date of next anti-myeloma treatment or until death.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Median (95% Confidence Interval); Unit of Measure: months
	11.04 [1]; (NA to NA)	NA [2]; (4.40 to NA)

[1]

The 95% CI was not available due to insufficient numbers of participants with events.

[2]

The median TTNT was not reached in Arm B and the upper confidence limit was not available due to insufficient numbers of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0384
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.224
	Confidence Interval	(2-Sided) 95%; 0.047 to 1.056
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from randomization to death due to any cause.
Time Frame	From the date of randomization until the end of study (approximately 12 months).

Outcome Measure Data

Analysis Population Description

Analysis was performed using the Full Analysis Set (FAS).

Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)
Arm/Group Description:	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7
Overall Number of Participants Analyzed	27	27
Median (95% Confidence Interval); Unit of Measure: months
	11.04 [1]; (NA to NA)	NA [2]; (NA to NA)

[1]

The 95% CI is not available due to insufficient numbers of participants with events.

[2]

The median OS was not reached in Arm B and the 95% CI was not available due to insufficient numbers of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Melflufen+Dexamethasone+Daratumumab), Arm B (Daratumumab)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3721
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.086 to 2.569
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events (AEs) were collected from the start of study treatment until 30 days after the last dose of study drug or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from signing of the informed consent form (ICF) until 30 days after the last dose of study treatment or initiation of subsequent therapy whichever occurred first. The maximum duration of treatment was 48 weeks, and the maximum duration of AEs/SAEs collection was 48 weeks + 30 days.
Adverse Event Reporting Description	AE definition: An AE is any untoward medical occurrence in a patient or clinical study patient, temporally associated with the use of study treatment, whether or not considered related to the study treatment. AEs are grouped by MedDRA system organ class (SOC) and preferred term (PT).
Arm/Group Title	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)	Crossover (From Arm B to the Same Treatment as Arm A)
Arm/Group Description	Treatment was given in 28-day cycles in an outpatient treatment setting.; Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle; Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years); Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Treatment was given in 28-day cycles in an outpatient treatment setting. • Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7	Patients in Arm B were allowed to crossover and receive the same treatment as Arm A after a confirmed disease progression (2 patients crossed over).
All-Cause Mortality
	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)	Crossover (From Arm B to the Same Treatment as Arm A)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/22 (9.09%)	3/26 (11.54%)	1/2 (50.00%)
Serious Adverse Events
	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)	Crossover (From Arm B to the Same Treatment as Arm A)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/22 (27.27%)	12/26 (46.15%)	1/2 (50.00%)
Blood and lymphatic system disorders
Anaemia †	2/22 (9.09%)	3/26 (11.54%)	0/2 (0.00%)
Pancytopenia †	1/22 (4.55%)	0/26 (0.00%)	0/2 (0.00%)
Gastrointestinal disorders
Enterocolitis †	1/22 (4.55%)	0/26 (0.00%)	0/2 (0.00%)
Gingival bleeding †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Rectal haemorrhage †	1/22 (4.55%)	0/26 (0.00%)	0/2 (0.00%)
General disorders
Death †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Disease progression †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Pain †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Infections and infestations
Pneumonia †	2/22 (9.09%)	2/26 (7.69%)	1/2 (50.00%)
Asymptomatic COVID-19 †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
COVID-19 pneumonia †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Injury, poisoning and procedural complications
Femur fracture †	0/22 (0.00%)	2/26 (7.69%)	0/2 (0.00%)
Upper limb fracture †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Metabolism and nutrition disorders
Hypercalcaemia †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Psychiatric disorders
Confusional state †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Renal and urinary disorders
Acute kidney injury †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
Vascular disorders
Hypotension †	0/22 (0.00%)	1/26 (3.85%)	0/2 (0.00%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm A (Melflufen+Dexamethasone+Daratumumab)	Arm B (Daratumumab)	Crossover (From Arm B to the Same Treatment as Arm A)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	21/22 (95.45%)	22/26 (84.62%)	2/2 (100.00%)
Blood and lymphatic system disorders
Neutropenia †	13/22 (59.09%)	8/26 (30.77%)	1/2 (50.00%)
Anaemia †	12/22 (54.55%)	7/26 (26.92%)	1/2 (50.00%)
Thrombocytopenia †	12/22 (54.55%)	4/26 (15.38%)	0/2 (0.00%)
Lymphopenia †	1/22 (4.55%)	2/26 (7.69%)	0/2 (0.00%)
Gastrointestinal disorders
Diarrhea †	2/22 (9.09%)	1/26 (3.85%)	0/2 (0.00%)
Nausea †	2/22 (9.09%)	0/26 (0.00%)	1/2 (50.00%)
General disorders
Pyrexia †	2/22 (9.09%)	3/26 (11.54%)	0/2 (0.00%)
Fatigue †	2/22 (9.09%)	0/26 (0.00%)	0/2 (0.00%)
Infections and infestations
Pneumonia †	2/22 (9.09%)	3/26 (11.54%)	1/2 (50.00%)
Infection †	2/22 (9.09%)	2/26 (7.69%)	0/2 (0.00%)
Upper respiratory tract infection †	2/22 (9.09%)	1/26 (3.85%)	0/2 (0.00%)
Injury, poisoning and procedural complications
Femur fracture †	0/22 (0.00%)	2/26 (7.69%)	0/2 (0.00%)
Investigations
Neutrophil count decrease †	3/22 (13.64%)	0/26 (0.00%)	0/2 (0.00%)
Platelet count decrease †	2/22 (9.09%)	1/26 (3.85%)	0/2 (0.00%)
SARS-CoV-2 test positive †	0/22 (0.00%)	2/26 (7.69%)	0/2 (0.00%)
Metabolism and nutrition disorders
Decreased appetite †	2/22 (9.09%)	0/26 (0.00%)	0/2 (0.00%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain †	0/22 (0.00%)	0/26 (0.00%)	1/2 (50.00%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

This study was put on clinical hold and later discontinued prematurely. Due to this, there is limited data available, and data cleaning was not done according to the original plan. Due to the early termination, the response assessments were done by investigators, not by an independent review committee.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: VP Chief Operating Officer
• Organization: Oncopeptides AB
• Phone: +46 8 615 20 40
• EMail: trials@oncopeptides.com

• Responsible Party: Oncopeptides AB
• ClinicalTrials.gov Identifier: NCT04649060
• Other Study ID Numbers: OP-108; 2019-002161-36 ( EudraCT Number )
• First Submitted: November 24, 2020
• First Posted: December 2, 2020
• Results First Submitted: February 7, 2023
• Results First Posted: June 8, 2023
• Last Update Posted: June 8, 2023