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

Study Overview
=================
Brief Summary
-----------------
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease.

Official Title
-----------------
A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in Combination With Daratumumab Compared With Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma

Conditions
-----------------
Relapsed Multiple Myeloma, Relapsed-Refractory Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Melflufen
* Drug: Dexamethasone
* Drug: Daratumumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A prior diagnosis of multiple myeloma with documented disease progression after the last line of therapy Double refractory to an IMiD and a PI (regardless of the number of prior lines of therapy) or have received at least 3 prior lines of therapy including an IMiD and a PI Prior treatment with daratumumab or another anti-CD38 antibody may be allowed under certain circumstances: Achieved at least partial response (PR) and not refractory to an anti-CD38 antibody At least 6 months since the last dose of anti-CD38 antibody Not discontinued anti-CD38 antibody treatment due to related Grade ≥ 3 toxicity Male and female of childbearing potential agree to use contraception during the treatment period and at least 3 months after the last dose Exclusion Criteria: Primary refractory disease (i.e., never responded with at least Minimal Response to any prior therapy for multiple myeloma) Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies Any medical condition that may interfere with safety or participation in this study Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast, or very low and low-risk prostate cancer in active surveillance Known or suspected amyloidosis, plasma cell leukemia, or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Known central nervous system (CNS) or meningeal involvement of myeloma Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy or prior allogeneic stem cell transplantation with active graft-versus-host-disease Prior treatment with melflufen

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (melflufen+dexamethasone+daratumumab)<br>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 | Drug: Melflufen<br>* Powder for solution for i.v. infusion<br>* Other names: Pepaxti;Drug: Dexamethasone<br>* Oral tablets<br>* Other names: Dex;Drug: Daratumumab<br>* Solution for s.c. injection<br>* Other names: Darzalex FASPRO;|
| Active Comparator: Arm B (daratumumab)<br>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 | Drug: Daratumumab<br>* Solution for s.c. injection<br>* Other names: Darzalex FASPRO;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | 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. | From the date of randomization until the end of study (approximately 12 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | 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). | From the date of randomization until the end of study (approximately 12 months). | 
| Duration of Response (DOR) | 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. | From the date of randomization until the end of study (approximately 12 months). | 
| Best Response | Proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD, or non-evaluable (NE). | From the date of randomization until the end of study (approximately 12 months). | 
| Clinical Benefit Rate (CBR) | The proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR, or MR. | From the date of randomization until the end of study (approximately 12 months). | 
| Duration of Clinical Benefit (DOCB) | 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. | From the date of randomization until the end of study (approximately 12 months). | 
| Time to Response (TTR) | Time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥PR. | From the date of randomization until the end of study (approximately 12 months). | 
| Time to Progression (TTP) | Time from randomization to the date of the first documented confirmed PD | From the date of randomization until the end of study (approximately 12 months). | 
| Time to Next Treatment (TTNT) | Time from randomization to the date of next anti-myeloma treatment or until death. | From the date of randomization until the end of study (approximately 12 months). | 
| Overall Survival (OS) | Time from randomization to death due to any cause. | From the date of randomization until the end of study (approximately 12 months). |