Despite the significant improvement in survival outcomes of multiple myeloma (MM) over the past decade, it remains an incurable disease.

Patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen has transformed the treatment armamentarium of relapsed/refractory MM (RRMM), with unprecedented overall response rates in this difficult-to-treat patient population. However, a significant proportion of patients ultimately relapse despite achieving deep remission.

Several innovative approaches, including alternative/dual-antigen–specific CAR T-cell constructs, genetically engineered “off-the-shelf” CAR T cells, and strategies to counteract an immunosuppressive microenvironment, may dramatically reshape the field of CAR T-cell therapy in the future.

These strategies are being actively investigated in preclinical and early clinical trial settings with the hopes of enhancing the durability of responses and, thereby, improving the overall survival of RRMM patients after CAR T-cell therapy.

In this paper published in Hematology, Kitsada Wudhikarn and Sham Mailankody of Memorial Sloan Kettering Cancer Center, New York and Eric L. Smith of Dana-Farber Cancer Institute, Harvard Medical School, Boston analyse the potential future applications of CAR-T cells in MM.

Analysed aspects are the following:

1. Overcoming antigen loss: beyond BCMA and polyspecific CAR
   T-cell constructs

2. Impeding host immune response: decreasing CAR antigenicity
and combating suppressive TME

3. Universal adoptive engineered cellular therapy: allogeneic and
iPSC-derived immune effector cells

4. Strategies to overcome intrinsic T-cell defects