Melflufen for relapsed and refractory multiple myeloma

ABSTRACT

Introduction

The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma.

Areas covered

This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described.

Expert opinion

Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.

KEYWORDS:

• Melflufen
• melphalan flufenamide
• relapsed/refractory multiple myeloma

Article Highlights

• Patients with multiple myeloma that are refractory to multiple agents with distinct mechanisms of action have limited treatment options, face universally poor outcomes, and are in urgent need of novel therapeutics.

• Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells.

• Melflufen has demonstrated potent cytotoxic activity in vitro in multiple myeloma cells, including those with resistance to other treatments (e.g., immunomodulatory drugs, proteasome inhibitors, and alkylators), and induces irreversible DNA damage and apoptosis.

• Melflufen in combination with dexamethasone has demonstrated clinically meaningful efficacy in patients with heavily pretreated relapsed/refractory multiple myeloma, including in patients with triple-class–refractory disease and those with extramedullary disease.

• Melflufen has demonstrated a well-established safety profile with clinically manageable hematologic adverse events being most common.

Acknowledgments

The authors received medical writing support from Jennifer Leslie PhD, Team 9 Science.

Declaration of interest

A Oriol has consultancy/advisory roles with Amgen, Janssen, Takeda, and Celgene; A Larocca has received honoraria from Amgen, Bristol-Myers Squib, Celgene, and Janssen-Cilag; X Leleu; has received honoraria from AbbVie, Amgen, Carsgen, Celgene, Gilead, Janssen, Karyopharm, Mundipharma, Novartis, Oncopeptides, and Takeda; R Hajek has received honoraria and has sconsultancy/advisory roles with Takeda, Amgen, Celgene, Janssen, and Bristol-Myers Squib and research funding from Takeda, Amgen, Janssen, and Novartis; H Hassoun has Consultancy/advisory roles with Novartis and receives research funding from Celgene and Janssen; PR Otero received honoraria from Celgene, Janssen, Amgen, and Bristol-Myers Squib and consultancy/advisory roles with Celgene, Janssen, Kite Pharma, Sanofi, Abbvie, Oncopeptides, GSK, and Takeda; A Paner received honoraria from Amgen and Celgene and has consultancy/advisory roles with AbbVie, Cellectar, and Takeda; FH Schjesvold received honoraria from Amgen, Celgene, Takeda, Janssen, Novartis, and SkyliteDx and has consultancy/advisory roles with Amgen, Celgene, Takeda, Janssen, Oncopeptides, and MSD; J Gullbo is co-founder and is a minor shareholder of Oncopeptides and has consultancy/advisory roles with Oncopeptides; PG Richardson has received a grant from Bristol-Myers Squib and grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm; and honoraria (advisory committee member) from Janssen, Sanofi, and SecuraBio. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer sat on an advisory board regarding melflufen in August 2019 and was involved in preclinical research at the non-profit Institute for Myeloma & Bone Cancer Research (IMBCR) on melflufen which was supported by Oncopeptides, Sweden. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Oncopeptides, Sweden which is the company that is developing melflufen.