A new decade: novel immunotherapies on the horizon for relapsed/refractory multiple myeloma

ABSTRACT

Introduction

Survival in multiple myeloma (MM) has improved due to the ongoing revolution of therapeutic approaches. Nevertheless, many patients relapse, and additional novel approaches are required to prolong remissions and prevent disease progression.

Areas Covered

Considering the success of monoclonal antibodies (mAbs) against CD38 and SLAMF7 in relapsed/refractory MM (R/R MM), additional antigens expressed on malignant plasma cells are being investigated as treatment targets. Among these, many trials are focusing on B cell maturation antigen (BCMA), using either antibody-drug conjugates (ADCs), bispecific T cell engagers (TCE), or chimeric antigen receptor T cells (CAR-T). Other potential targets include the myeloma markers CD138, GPRC5D, FcRH5, the plasma cell differentiating factors APRIL, TACI and BAFF, and the immune checkpoint proteins CD47 and TIGIT. Additionally, novel immunomodulatory Cereblon E3 Ligase Modulators (CELMoDs) offer the potential to overcome resistance to conventional immunomodulatory agents. Based upon PubMed and abstract searches primarily from the past 4 years, here we review the data supporting novel immunotherapies for R/R MM.

Expert opinion

Overcoming disease resistance remains a challenge in R/R MM. Novel therapeutic approaches targeting MM antigens and/or enhancing immune cell function offer the potential to prolong survival and are actively being investigated in clinical trials.

KEYWORDS:

• Multiple myeloma
• immunotherapies
• monoclonal antibodies
• antibody-drug conjugates
• bispecific antibodies
• car-t cells

Article highlights

• Overcoming drug resistance remains a challenge in R/R MM.

• Despite the presence of immune dysfunction and genetic complexity in R/R MM, immune-based therapies are able to induce remissions.

• Immune-based approaches include monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bispecific T cell engagers (TCE), chimeric antigen receptor T cells (CAR-T), and immunomodulatory therapies.

• Established and novel targets include plasma cell-specific markers such as CD38, SLAMF7, BCMA, GPRC5D and FcRH5, as well, as T cell, macrophage, and NK cell markers to enhance immune cell function.

• Early clinical reports demonstrate that response rates of novel immunotherapies are high with many complete responses and evidence of minimal residual disease negativity.

• Side effect profiles of novel immunotherapies in MM, including TCEs and CAR-T cells, are different from traditional MM treatments and need to be expectantly managed.

• Ongoing studies will confirm the efficacy and side effect profile of each modality and will explore the most appropriate positions for these modalities in the MM patients during their treatment journey.

• The array of immune approaches with different mechanisms of action and side effects offers the potential for individualized approaches based on the characteristics of the patients’ MM cells, their BM microenvironment, co-morbidities, and lifestyle choices.

• Given the efficacy of these novel immunotherapeutic approaches in R/R MM, results of their use in earlier lines of therapy are eagerly awaited.

Declaration of interest

M Braunstein has received research funding from Celgene and Janssen and has served on advisory boards for Adaptive Biotechnologies, Amgen, AstraZeneca, Celgene, Janssen, Karyopharm, Morphosys, Takeda, TG Therapeutics, and Verastem. F Davies has received research funding from Celgene and Janssen and has served on advisory boards for Abbvie, Amgen, BMS, Genetech, Janssen, Oncopeptide, Roche, Sanofi, Takeda. 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.