Antibody-drug conjugates, bispecific antibodies and CAR-T cells therapy in multiple myeloma

ABSTRACT

Introduction

Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach deep level of responses and extend survival outcomes.

Areas covered

Antibody-drug conjugates (ADCs) and T-cell redirecting treatments, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells therapy, have been recently introduced in the treatment of RRMM. Some agents have already received regulatory approval, while newer constructs, novel combinations, and applications in earlier lines of therapy are currently being explored. This review discusses the current landscape and possible development of ADCs, BsAbs and CAR-T cells immunotherapies.

Expert Opinion

ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, triple-class exposed (TCE) MM patients, and T-cell redirecting treatments represent new standards of care after third (European Medicines Agency, EMA), or fourth (Food and Drug Administration, FDA), line of therapy. All these three immunotherapies carry advantages and disadvantages, with different accessibility and new toxicities that require appropriate management and guidelines. Multiple on-going programs include combinations therapies and applications in earlier lines of treatment, as well as the development of novel agents or construct to enhance potency, reduce toxicity and facilitate administration. Sequencing is a challenge, with few data available and mechanisms of resistance still to be unraveled.

KEYWORDS:

• Multiple myeloma
• immunotherapy
• antibody-drug conjugates
• bispecific antibodies
• chimeric antigen receptor T cells therapy

Article highlights

• ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, TCE RRMM patients, major targets including BCMA, GPRC5D and FcRH5.

• A phase 2 study has demonstrated the efficacy of the BCMA-targeting ADC belantamab mafodotin monotherapy for the treatment of TCR RMM.

• Different phase 1/2 or 2 studies have demonstrated the efficacy of the BCMA-targeting BsAbs teclistamab and elranatamab, as well as of the GPRC5D-targeting BsAb talquetamab, for the treatment of TCE RMM, resulting in regulatory approval.

• Phase 2 or 1/2 studies have demonstrated the efficacy of two anti-BCMA CAR-T cell therapies, ide-cel and cilta-cel, for the treatment of TCE RRMM, resulting in regulatory approval.

• These novel immunotherapy approaches have some differences in terms of efficacy, toxicities, accessibility, dosing and administration, that may be used to guide a correct therapeutic choice.

• Ongoing and planned clinical trials will evaluate the use of treatment combinations, application in earlier lines of therapy, as well as newer constructs and products, with the aim of increasing efficacy, and mitigating toxicity.

Declaration of interest

P Tacchetti has received honoraria from Amgen, Bristol-Myers Squibb/Celgene, Janssen, Takeda, AbbVie, Sanofi, GlaxoSmithKline and Pfizer; L Pantani has received honoraria from GlaxoSmithKline, Sanofi and Pfizer; K Mancuso has received honoraria from Celgene, Takeda, Amgen, Sanofi and Janssen; I Rizzello has received honoraria from Amgen, GlaxoSmithKline and Sanofi and advisory role for GlaxoSmithKline; E Zamagni has received honoraria from Janssen, Bristol-Myers Squibb, Amgen, Takeda; M Cavo has served as Consulting/advisory role for and has received honoraria from Amgen, AbbVie, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, Menarini Stemline, Sanofi, and Karyopharm Therapeutics. 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work was funded by the Italian Ministry of Health, RC-2023-2778909