Chimeric antigen receptor T (CAR-T) cell therapy is a form adoptive T cell therapy where host T cells are transduced with a chimeric antigen receptor (CAR) composed of an antibody-derived single-chain variable fragment (ScFv), hinge domain, transmembrane domain, co-stimulatory signals, and the CD3 zeta chain. The ScFv have high affinity to a specific tumor associated antigen (TAA) which helps target cell binding whereas the intracellular domain plays an important role in T-cell activation and cytotoxicity in an MHC independent manner. The intracellular domain consists of a primary (commonly CD3zeta) and secondary co-stimulatory domain (eg. CD28, 41-BB) [1]. As part of CAR-T generation, patients undergo leukapheresis followed by T cell enrichment and activation. These activated T cells are then transduced (eg with viral vector) to express the CAR(s). These CAR-T cells then undergo a period of expansion before being re-introduced to the patient after completing lymphodepleting chemotherapy. This period from leukapheresis to CAR-T administration varies by the CAR-T product used but on average takes about 4–6 weeks. The CAR-T cells once administered to the patient, can identify, and bind the tumor cells, cause T-cell activation and expansion, and cause tumor cell killing by various mechanisms. These include release of cytotoxic molecules- granzymes and perforins, cytokine production, induction of apoptosis via the FAS ligand pathway as well as activation of native lymphocytes and other immune cells [2]. CAR-T cells are also associated with unique toxicities like cytokine release syndrome (CRS), immune effector cell associated neurotoxicity (ICANS), hemophagocytic lymphohistiocytosis (HLH), infections as well as other delayed toxicities.

Multiple myeloma (MM) is a plasma cell neoplasm which accounts for approximately 10 % of all hematological malignancies. It is defined by presence of clonal bone marrow plasmacytosis causing monoclonal gammopathy with myeloma defining events like anemia, hypercalcemia, renal insufficiency and lytic bone lesions (CRAB criteria). In 2014, additional myeloma defining biomarkers were included such as involved light chain of≥100 mg/dL for patients with free light chain ratio of≥100 and presence of >60 % bone marrow plasma cells [3]. It is a heterogenous disease classified into risk categories based on cytogenetic abnormalities [4]. Significant advances in the field have led to development of excellent therapies improving the survival outcomes significantly over the last two decades. These include immunomodulatory drugs (IMIDs), proteosome inhibitors (PIs) and anti-CD38 monoclonal antibodies. In eligible patients, high dose chemotherapy with autologous hematopoietic cell rescue remains an important therapeutic tool which has consistently shown improvement in progression free survival (PFS) as compared to combination biological therapy alone although impact on overall survival (OS) remains uncertain [5]. However, despite these significant advances, patients ultimately develop progressively resistant disease with poor outcomes. Patients with triple class refractory disease (IMiD, PI and anti-CD38 mAb) have poor response rates to most standard of care therapies and a short PFS (4.6 months) and overall survival (12.4 months) [6].

B-cell maturation antigen (BCMA) or CD269 is a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligands include B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) which has a higher affinity to BCMA. BCMA is highly expressed by malignant plasma cells compared to other bone marrow mononuclear cells like normal plasma and terminally differentiated B cells [7,8]. BCMA has served as an important target for development of targeted and immunotherapies. BCMA directed therapies have proved revolutionary and have improved the outcomes of patients with refractory myeloma significantly. These include Chimeric Antigen Receptor T cell (CAR-T) therapy directed against BCMA, CD3xBCMA bispecific monoclonal antibodies as well as BCMA directed antibody drug conjugates. A major limitation for these effective therapies being given in later lines (>3) is high treatment attrition related to disease progression making patients unfit. There is an increasing effort to move these treatments in earlier lines of therapy. Recently CAR-T therapy was approved as second line treatment for relapsed myeloma.

Immune dysregulation is a hallmark of multiple myeloma which is even more pronounced in the relapsed/refractory setting. Therefore, targeting the immune landscape is an attractive therapeutic strategy [9]. As mentioned, there are two anti-BCMA CAR-T cell products approved for the use in relapsed myeloma (Table 1) whereas there are multiple other CAR-T cells with a different myeloma associated target antigen or CAR construct under investigation. This review will focus on the current state of CAR-T cell therapy in multiple myeloma (Fig. 1).