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

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

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.

Study Overview

• Status: Terminated
• Conditions: Relapsed Multiple Myeloma; Relapsed-Refractory Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Drug: Melflufen; Drug: Daratumumab

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria
    • University Multiprofile Hospital for Active Treatment "Sveti Georgi", Plovdiv, Clinical Hematology Clinic
  • Sofia, Bulgaria
    • Specialized Hospital for Active Treatment of Hematological Diseases, Clinical Hematology Clinic
• Czechia
  • Brno, Czechia, 62500
    • University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology
  • Kralovice, Czechia
    • University Hospital Hradec Kralove, 4th Internal Clinic of Hematology
  • Ostrava-Poruba, Czechia
    • University Hospital Ostrava, Clinic of Hematooncology
  • Prague, Czechia
    • General University Hospital in Prague, 1st Internal Clinic - Clinic of Hematology
• Georgia
  • Tbilisi, Georgia
    • JSC K. Eristavi National Center of Experimental and Clinical Surgery
  • Tbilisi, Georgia
    • Malkhaz Katsiashvili Multiprofile EMC LTD
• Germany
  • Siegen, Germany
    • St. Marien-Hospital Siegen gem. GmbH, Clinic for Hematology, Medical Oncology and Palliative Medicine
• Greece
  • Athens, Greece
    • General Hospital of Athens "Evangelismos", Department of Hematology and Lymphoma
  • Athens, Greece
    • Alexandra General Hospital, Therapeutic Clinic
• Norway
  • Oslo, Norway
    • Oslo University Hospital, Ulleval University Hospital, Oslo Myeloma Center
• Poland
  • Chorzów, Poland
    • Independent Public Healthcare Facility Municipal Hospitals, Teaching Department of Hematology And Prevention of Neoplastic Diseases
  • Gdańsk, Poland
    • University Clinical Center, Teaching Department of Hematology and Transplantology
  • Kraków, Poland
    • Independent Public Healthcare Facility University Hospital in Krakow, Teaching Unit of the Hematology Department
  • Lodz, Poland
    • Nicolaus Copernicus Provincial Multispecialty Oncology and Traumatology Center in Lodz
  • Lublin, Poland
    • St. John of Dukla Oncology Center of Lublin Region, Department of Hematology and Bone Marrow Transplantation
• Russian Federation
  • Saint Petersburg, Russian Federation
    • Leningrad Regional Clinical Hospital
  • Samara, Russian Federation
    • V.D. Seredavin Samara Regional Clinical Hospital
• Serbia
  • Belgrade, Serbia
    • Clinical Center of Serbia
• Spain
  • Barcelona, Spain
    • Hospital Clinic of Barcelona, Department of Hematology
• Ukraine
  • Cherkasy, Ukraine
    • Cherkasy Regional Oncology Dispensary, Regional Treatment and Diagnostic Hematology Center
  • Chernihiv, Ukraine
    • Chernihiv Medical Center of Modern Oncology, Hematology Department
  • Dnipro, Ukraine
    • City Clinical Hospital No. 4 City Hematology Center
  • Kyiv, Ukraine
    • National Institute of Cancer, Research Department of Hemoblastosis Chemotherapy and Adjuvant Treatment Methods, Department of Oncohematology with Adjuvant Treatment Methods Group
  • Kyiv, Ukraine
    • Kyiv City Clinical Hospital No. 9, Hematology Department No. 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (melflufen+dexamethasone+daratumumab); 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: Dexamethasone; Oral tablets; Other Names: Dex; Drug: Melflufen; Powder for solution for i.v. infusion; Other Names: Pepaxto; Melphalan Flufenamide; Pepaxti; Drug: Daratumumab; Solution for s.c. injection; Other Names: Darzalex FASPRO
Active Comparator: Arm B (daratumumab); 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; Solution for s.c. injection; 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).

Collaborators and Investigators

• Sponsor: Oncopeptides AB
• Investigators: Principal Investigator: Maria-Victorìa Mateos, MD, PhD, Complejo Hospitalario de Salamanca

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2020
• Primary Completion (Actual): February 7, 2022
• Study Completion (Actual): February 7, 2022

Study Registration Dates

• First Submitted: November 24, 2020
• First Submitted That Met QC Criteria: November 24, 2020
• First Posted (Actual): December 2, 2020

Study Record Updates

• Last Update Posted (Actual): June 8, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Daratumumab; Melphalan
• Other Study ID Numbers: OP-108; 2019-002161-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No