BCMA-targeted therapies for multiple myeloma: strategies to maximize efficacy and minimize adverse events

ABSTRACT

Introduction

Immunotherapies targeting B cell maturation antigen (BCMA) in multiple myeloma are transitioning through trials and entering the clinic, and will likely become a core pillar in myeloma therapeutics. These agents demonstrate unprecedented activity in multiply relapsed patients, but notwithstanding the short follow-up times their survival curves do not appear to demonstrate a plateau, and the treatments inevitably bring with them a range of toxicities that might be associated with tolerability issues.

Areas covered

We will briefly lay out the current therapeutic landscape in multiple myeloma, before introducing BCMA and explaining its significance. We will address in turn the three key classes of anti-BCMA immunotherapies: antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells. We describe the mechanisms of action of these classes and review the evidence supporting their efficacy and toxicities. We then bring all three therapies into one discussion that explores how to mitigate toxicities and overcome myeloma’s ability to resist these potent treatments.

Expert opinion

Finally, we take the discussion back to the clinic, and consider how we might deploy anti-BCMA therapies most effectively for our patients. We consider the sequencing of treatment, and what further evidence is needed to more fully inform our therapy decisions.

KEYWORDS:

• Antibody-drug conjugates
• BCMA – B cell maturation antigen
• bispecific antibodies
• CAR T cells – chimeric antigen receptor T cells
• therapy resistance
• toxicity

Article highlights

• B cell maturation antigen (BCMA) is an exciting target for therapy in multiple myeloma, owing to its relative specificity and important role in myeloma development and progression.

• Antibody drug conjugates include the first anti-BCMA therapy to be licensed, Belantamab mafodotin, which demonstrates efficacy as a single agent in relapsed/refractory myeloma, at the expense of corneal toxicity by as-yet unclear mechanisms.

• No bispecific antibody targeting BCMA has yet been licensed, but they represent a competitive and exciting class with significant potential but considerable toxicity profile.

• Chimeric antigen receptor T cells demonstrate the deepest responses, but carry an accordingly higher risk of toxicity, especially through cytokine release, infections, cytopenias, and neurotoxicity syndromes.

• Toxicities – keratopathy, cytokine release syndrome, and neurotoxicities – are still relatively poorly understood, and could be better mitigated with further studies, and require adoption of consensus guidance by clinicians.

• There are potential avenues for overcoming therapy resistance – for instance, including therapy earlier in the disease timeline – but most are experimental, and based on an incomplete understanding of the mechanisms of actions of these therapies and of the tumor microenvironment.

• BCMA-targeting therapy in the myeloma treatment paradigm is established. Our next steps should focus on optimizing efficacy and toxicity, which will require a deep understanding of therapeutic mechanisms and resistance.

Declaration of interest

K Ramasamy reports support from: Celgene: Research support, Speaker’s fees, Advisory board, Travel; Takeda: Research support, Speaker’s fees, Advisory board, Travel; Janssen: Research support, Speaker’s fees, Advisory board, Travel; Amgen: Research support, Advisory board, Travel; Abbvie: Advisory board; Sanofi: Speaker’s fees, Advisory board; Oncopeptides: Speaker’s fees, Advisory board; Karyopharm: Advisory board; GSK: Research support, Speaker’s fees, Advisory board; Adaptive biotech: Speaker’s fees, Advisory board; Pfizer: Advisory board.

F Djebbari reports support from Sanofi: Speaker’s fees; Takeda: Support with conference attendance.

A Rampotas reports support from Gilead: Support with conference attendance.

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 apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript is an investigator on cartitude, AMG701 and other CarT and BSA studies sponsored by Janssen, Amgen CRISPR. I have received honoraria from Janssen Amgen BMS and Novartis. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.