CD38 as an immunotherapeutic target in multiple myeloma

ABSTRACT

Introduction: Multiple myeloma (MM) is a currently incurable hematologic tumor with heterogeneous clinical behavior and prognosis. During the last years, survival improved due to a better understanding of MM biology and the development of novel drugs, although it still remains unsatisfactory in many cases: new drugs and treatment strategies are needed. CD38 is uniformly expressed at high levels on MM cells and, to a lesser extent, on the surface of normal hematopoietic and non-hematopoietic cells, making this molecule an interesting target for immunotherapeutic approaches.

Areas covered: This review discusses the preclinical and clinical experience on different immunotherapeutic agents targeting CD38 in MM.

Expert commentary: Monoclonal antibodies (mAbs) targeting CD38 are currently changing the treatment scenario in MM, allowing physicians to reach unprecedented results, especially when anti-CD38 mAbs are used in combination with consolidated MM treatments. Other immunotherapies targeting CD38 – such as conjugated anti-CD38 mAbs, bispecific antibodies stimulating T cells to eliminate CD38+ MM cells, and CD38-specific chimeric antigen receptor T cells – are interesting strategies, currently at earlier developmental stages.

KEYWORDS:

• CD38
• monoclonal antibodies
• bispecific antibodies
• drug conjugates
• CAR T cells
• multiple myeloma

Article highlights

• CD38 surface antigen is highly expressed on myeloma plasma cells as well as on other immune system cells and is therefore a key target for immunotherapeutic agents.

• Mechanisms of action of anti-CD38 monoclonal antibodies (mAbs) include antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cell-mediated phagocytosis, as well as immunomodulatory effects on tumor microenvironment.

• Anti-CD38 action is enhanced by other compounds, such as immunomodulatory agents and proteasome inhibitors in preclinical models.

• Daratumumab is the first anti-CD38 mAb showing high efficacy and favorable toxicity profile in clinical trials as monotherapy and in combinations with the currently approved standard regimens for myeloma treatment.

• Daratumumab main toxicity consists of infusion-related reactions (IRRs), mainly involving the upper respiratory tract. Careful selection of patients and appropriate infusion premedication are the keys to avoid severe IRRs, which, however, are uncommon.

• Other anti-CD38 mAbs (isatuximab, MOR202, and TAK-079) are currently being evaluated in clinical trials. CD38 drug conjugates, bispecific antibodies and chimeric antigen receptor T cells are also under investigation in multiple myeloma.

This box summarizes key points contained in the article.

Declaration of interest

M Boccadoro has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, AbbVie, Bristol-Myers Squibb, research funding from Celgene, Janssen, Amgen, Bristol-Myers Squibb, Mundipharma, Novartis, and Sanofi. F Gay has received honoraria from Takeda, Amgen, Celgene, Janssen, Bristol-Myers Squibb, and served on the advisory board for Takeda, Seattle Genetics, Celgene, and Roche. 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

One of the reviewers has received grant support from companies Genmab, Jannsen and Takeda, which are developing (or have already developed) CD38 antibody-based therapies. Other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.