Chimeric Antigen Receptor T Cells for the Treatment of Multiple Myeloma

In 2015, the U.S. Food and Drug Administration (FDA) approved four drugs with novel mechanisms for the treatment of multiple myeloma (MM): panobinostat, daratumumab, elotuzumab, and ixazomib. The evolving treatment strategies and rapid increase in offerings are perhaps unmatched in the recent history of drug development for hematologic malignancies. However, MM remains an incurable malignancy. Novel immunotherapies, such as chimeric antigen receptor (CAR) T cells, B-cell–specific monoclonal antibodies, and checkpoint inhibitors, are promising therapies that are helping to advance the field.

As reported by Dr. Marcela V. Maus and colleagues, transduction of autologous T cells to express CD-19–specific CARs is a promising immunotherapeutic approach for the treatment of B-cell cancers.¹  In a case report published in the New England Journal of Medicine, Dr. Alfred L. Garfall and colleagues reported the outcome of autologous transplantation followed by treatment with CTL019 cells, which consist of autologous T cells expressing a CD3-zeta/CD137–based anti–CD-19 CAR from a lentiviral vector. The approach led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein when reported 12 months after treatment of a patient with refractory MM, who had received nine prior lines of therapy, including lenalidomide, bortezomib, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab.²  CD-19 is infrequently expressed on MM cells and is not generally considered a strong target. However, this and other reports suggest that there is a minor population of MM clones with drug-resistant, disease-propagating properties that have a B-cell phenotype (i.e., CD-19–positive).³  The efficacy of CAR T cells in this small subset of MM patients begs the question of whether there is a more MM-specific target to which this strategy may be applied.

B-cell maturation antigen (BCMA; CD269) is a member of the TNF receptor superfamily, TNFRSF17.⁴  Expression of BCMA is restricted to the B-cell lineage where it is predominantly expressed in the interfollicular region of germinal centers⁵  and on differentiated plasma cells⁶  and plasmablasts.⁷  BCMA is virtually absent on naïve and memory B cells^8,9  but it is selectively induced during plasma cell differentiation where it may support humoral immunity by promoting the survival of normal plasma cells and plasmablasts.

In a late-breaking abstract presented during the 2015 ASH Annual Meeting, Dr. Syed Abbas Ali and colleagues presented the first in-human clinical trial of T cells expressing anti-BCMA CAR T cells. Patients had advanced MM with a median of seven prior lines of therapy. Patients received a single infusion of CAR-BCMA T cells. Prior to CAR T-cell infusion, patients received 300 mg/m² cyclophosphamide and 30 mg/m² fludarabine to enhance activity of the CAR T cells by depleting endogenous leukocytes. Two patients were treated at the highest dose level: one attained a stringent complete response, and the other had a very good partial response. Both patients treated at the highest dose level experienced signs of cytokine release syndrome, including fever, tachycardia, hypotension, hypoxia, and coagulopathy. The toxicities were similar to those seen in leukemia patients treated with anti–CD-19 CAR T cells. This trial suggests that there may be strong anti-MM activity for CAR T cells targeting BCMA.

Humanized monoclonal antibodies against BCMA are another area of investigation showing great promise in the field.¹⁰  These and future studies will determine whether off-the-shelf approaches such as the use of monoclonal antibodies directed against BCMA, versus the more patient-specific CAR T-cell approaches, will yield better long-term disease control. The obvious advantage of BCMA-directed monoclonal antibodies is the easy access and potential lack of toxicity. However, with the use of tocilizumab, a humanized monoclonal antibody directed against interleukin-6 receptor, to treat CAR T cell–related cytokine release syndrome, and with better supportive care strategies, cellular therapies may also become better tolerated over time.