Checkpoint Inhibition in Myeloma: Opportunities and Challenges.

Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as "immune checkpoints") including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.