B cell maturation antigen (BCMA)-based immunotherapy for multiple myeloma

ABSTRACT

Introduction: B cell maturation antigen (BCMA) contributes to MM pathophysiology and is a target antigen for novel MM immunotherapy. Complete responses have been observed in heavily pretreated MM patients after treatment with BCMA antibody-drug conjugates (ADC), chimeric antigen receptor T, and bi-specific T cell engagers (BiTE®). These and other innovative BCMA-targeted therapies transform the treatment landscape and patient outcome in MM.

Areas covered: The immunobiological rationale for targeting BCMA in MM is followed by key preclinical studies and available clinical data on efficacy and safety of therapies targeting BCMA from recent phase I/II studies.

Expert opinion: BCMA is the most selective MM target antigen, and BCMA-targeted approaches have achieved high responses even in relapse and refractory MM as a monotherapy. Long-term follow-up and correlative studies using immuno-phenotyping and -sequencing will delineate mechanisms of overcoming the immunosuppressive MM bone marrow microenvironment to mediate additive or synergistic anti-MM cytotoxicity. Moreover, they will delineate cellular and molecular events underlying the development of resistance underlying relapse of disease. Most importantly, targeted BCMA-based immunotherapies used earlier in the disease course and in combination (adoptive T cell therapy, mAbs/ADCs, checkpoint and cytokine blockade, and vaccines) have great promise to achieve long-term disease control and potential cure.

KEYWORDS:

• Multiple myeloma (MM)
• B cell maturation antigen (BCMA)
• targeted immunotherapy
• monoclonal antibody (mAb)
• chimeric antigen receptor T cell (CAR T)
• antibody-drug conjugate (ADC)
• bi-specific T cell engager (BiTE)
• adoptive T cell therapy
• cancer vaccine
• bone marrow (BM) microenvironment
• minimal residual disease (MRD)

Article highlights

• B cell maturation antigen (BCMA) promotes MM pathogenesis in the BM microenvironment and is a very specific MM target antigen.

• Immunologically-based therapies targeting BCMA demonstrate promise independent of the genetic heterogeneity and genetic risk even in MM patients with no other treatment options.

• Immunotherapies targeting BCMA including antibody-drug conjugates (ADCs), autologous chimeric antigen receptor engineered T cells (CAR-T), and bispecific T cell engager (BiTE®) have achieved responses even in RRMM.

• The US FDA has granted Breakthrough Therapy Designation in 2017 to GSK for anti-BCMA ADC (GSK2857916/Belantamab mafodotin) auristatin immunotoxin and to Celgene/Bluebird Bio for anti-BCMA CAR-T therapy (bb2121/Idecabtagene vicleucel); as well as in 2018 to Poseida Therapeutics/Regenerative Medicine Advanced Therapy (RMAT) for P-BCMA-101 CAR-T cells, and to Amgen for anti-BCMA BiTE® (AMG 420).

• Although BCMA-targeted CAR-T cell therapy for MM has achieved remarkable responses even in advanced refractory disease, ongoing research is directed to increasing efficacy and prolonging responses, as well as improving safety and abrogating cytokine release syndrome (CRS)-related toxicity. Ocular toxicity and frequent infection are the major adverse events (AEs) reported in patients receiving GSK2857916 immunotoxin and AMG 420 BiTE®, respectively.

• Potentially more durable off-shelf BCMA-targeted immunotherapies include allogenic CAR T cells and BCMA-peptide vaccines/adoptive immunotherapy. Ultimately combination immune approaches will be needed to achieve optimal clinical benefit.

This box summarizes key points contained in the article.

Acknowledgments

We thank all laboratory and clinical research teams at the LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute for their continuous encouragement, help, and support.

Declaration of interest

KC Anderson serves on advisory boards to Celgene, Millennium, Janssen, Sanofi, Bristol Myers Squibb, Gilead, Precision Biosciences, and Tolero, and is a Scientific founder of OncoPep and C4 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 relationships or otherwise to disclose.

Additional information

Funding

This work was supported in part by grants from the National Institutes of Health Grants P50-100707, PO1-078378 and RO1-050947. KC Anderson is an American Cancer Society Clinical Research Professor. This work was supported in part by the Miriam and Sheldon G Adelson Medical Research Foundation.